subject:(human hepatocytes)

University of Alberta

1. Alsagheir, Ali I. Differentiation of human embryonic stem cells into hepatocytes and their in vivo application for hepatitis C viral production.

Degree: MS, Department of Surgery, 2014, University of Alberta

URL: https://era.library.ualberta.ca/files/c2j62s516f

► Abstract Introduction: Chronic hepatitis C virus (HCV) infection is a global problem. The World Health Organization estimates that about 170 million individuals around the world… (more)

▼ Abstract Introduction: Chronic hepatitis C virus (HCV) infection is a global problem. The World Health Organization estimates that about 170 million individuals around the world are infected with HCV. Chronic HCV has a high rate of morbidity and mortality due to cirrhosis and hepatocellular carcinoma. It is a major indication for liver transplantation. The current treatment is interferon α and ribavirin of which only 50% of cases show sustained virological responses and clinical signs of improvement, indicating the need for further exploration of novel anti HCV drugs 1. Several small animal models capable of supporting HCV infection in vivo have been achieved by the transplantation and expansion of primary human hepatocytes into the livers of mice2. The major limitations of these models are the generation of a supply of hepatocytes, which must come from human donors, and the technical difficulties associated with their isolation. Human embryonic stem cells (hESC) are pluripotent cells derived from the inner cell mass of blastocytes during early embryonic life 3. These cells are capable of self-regeneration and differentiation into any adult cell type in the human body. In the last few years, multiple centers around the world have successfully generated mature hepatocytes from human embryonic stem cells. Therefore, it is possible that hESCs can be used as a substitute for primary human hepatocytes in a small animal mouse model. Our primary objective was to explore the possibility of differentiating hESCs into hepatocyte-like cells that could be used as substitutes for primary human hepatocytes in an SCID/UPA mouse model. As such, these studies are expected to increase the accessibility and utility of the SCID/UPA mouse model for a variety of applications, including the testing of the efficacy of antiviral strategies targeting the HCV lifecycle. Methods: According to a published procedure4, human embryonic stem cells underwent a multi-stage differentiation protocol to render them hepatocyte-like. The successful transition of hESCs to hepatocytes was monitored by indirect immunofluorescence detection of various protein markers at each stage of the differentiation process. The ability of the differentiated human hepatocytes to engraft and support productive HCV infection was evaluated in vivo subsequent to their transplantation to the livers of SCID/UPA mice using procedures previously established in our lab. Results: Successful differentiation of hESCs into hepatocyte-like cells was demonstrated with indirect immunofluorescence. Thirty-five SCID/uPA mice were transplanted with undifferentiated hESCs (n=7), primary human hepatocytes (PHHs) (n=9), or differentiated human hepatocytes (DHHs) (n=19). After transplantation, serum analysis of mice from the DHH group showed undetectable levels of human alpha-1 antitrypsin (hAAT) and HCV viral production. By contrast, mice transplanted with PHH secreted hAAT values ranging from 229–1515 ng/ml, and 3 out of the 9 mice showed detectable HCV RNA levels. At the end point of the…

Subjects/Keywords: Human embryonic stem cells; Differentiated hepatocytes; Hepatitis C virus; Stem cells; Hepatocytes-like cells

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APA (6^th Edition):

Alsagheir, A. I. (2014). Differentiation of human embryonic stem cells into hepatocytes and their in vivo application for hepatitis C viral production. (Masters Thesis). University of Alberta. Retrieved from https://era.library.ualberta.ca/files/c2j62s516f

Chicago Manual of Style (16^th Edition):

Alsagheir, Ali I. “Differentiation of human embryonic stem cells into hepatocytes and their in vivo application for hepatitis C viral production.” 2014. Masters Thesis, University of Alberta. Accessed January 18, 2021. https://era.library.ualberta.ca/files/c2j62s516f.

MLA Handbook (7^th Edition):

Alsagheir, Ali I. “Differentiation of human embryonic stem cells into hepatocytes and their in vivo application for hepatitis C viral production.” 2014. Web. 18 Jan 2021.

Vancouver:

Alsagheir AI. Differentiation of human embryonic stem cells into hepatocytes and their in vivo application for hepatitis C viral production. [Internet] [Masters thesis]. University of Alberta; 2014. [cited 2021 Jan 18]. Available from: https://era.library.ualberta.ca/files/c2j62s516f.

Council of Science Editors:

Alsagheir AI. Differentiation of human embryonic stem cells into hepatocytes and their in vivo application for hepatitis C viral production. [Masters Thesis]. University of Alberta; 2014. Available from: https://era.library.ualberta.ca/files/c2j62s516f

Penn State University

2. Goyak, Katy M. O. Expression profiling of interindividual and interspecies variability in hepatic models. .

Degree: 2009, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/9046

► Although in vivo rodent models are a necessary part of the risk assessment process, incorporation of human models is necessary in order to evaluate whether… (more)

▼ Although in vivo rodent models are a necessary part of the risk assessment process, incorporation of human models is necessary in order to evaluate whether effects in rodents are applicable to humans. Studies with in vitro hepatocytes have been hindered by the dramatic loss of differentiation status and liver-specific functions after isolation. In this study, expression profiling analyses demonstrate that hepatocytes cultured in a sandwich configuration and in the presence of physiological levels of dexamethasone maintain expression levels of liver-enriched transcription factors, drug-metabolizing enzymes, and transporters similar to that in human liver tissues. Additionally, hepatocytes in these conditions exhibit a complex biological response after xenobiotic challenge, namely, induction of cytochrome P450 mRNA and protein, marking these cells as a robust model system for studies of drug metabolism. An additional complicating factor of using primary hepatocytes in risk assessment is the magnitude of interindividual variability in hepatocytes from different donors. This study presents a detailed analysis of the comparability of response genes in hepatocytes from ten donors after challenge with xenobiotics that exhibit distinct mechanisms of action. A gene to gene comparison shows that hepatocytes exhibit limited reproducibility in response genes across donors, although a comparison of functional categories significantly increases reproducibility. Using this functional category approach, profiling results in primary human hepatocytes were compared to profiling results in mice after treatment with the same xenobiotics. Conserved cross-species responses were consistent with literature-reported mechanisms for each chemical. Interestingly, mitochondrial oxidative metabolism genes, specifically those genes in the tricarboxylic acid cycle and the electron transport chain, were consistently decreased in mice but were often increased in primary human hepatocytes. Finally, expression profiling of phenobarbital response genes identified a novel gene, Tsukushin (TSKU) that was reproducibly increased after treatment in nine of the ten human hepatocyte donors. TSKU knockdown in primary human hepatocytes resulted in a diminished cytochrome P450 induction response through an indirect mechanism. Advisors/Committee Members: Curtis John Omiecinski, Dissertation Advisor/Co-Advisor, Curtis John Omiecinski, Committee Chair/Co-Chair, Pamela Hankey Giblin, Committee Member, Harriet C Isom, Committee Member, Mary J Kennett, Committee Member, Gary H Perdew, Committee Member.

Subjects/Keywords: DNA microarrays; human hepatocytes

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APA (6^th Edition):

Goyak, K. M. O. (2009). Expression profiling of interindividual and interspecies variability in hepatic models. . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/9046

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Goyak, Katy M O. “Expression profiling of interindividual and interspecies variability in hepatic models. .” 2009. Thesis, Penn State University. Accessed January 18, 2021. https://submit-etda.libraries.psu.edu/catalog/9046.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Goyak, Katy M O. “Expression profiling of interindividual and interspecies variability in hepatic models. .” 2009. Web. 18 Jan 2021.

Vancouver:

Goyak KMO. Expression profiling of interindividual and interspecies variability in hepatic models. . [Internet] [Thesis]. Penn State University; 2009. [cited 2021 Jan 18]. Available from: https://submit-etda.libraries.psu.edu/catalog/9046.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Goyak KMO. Expression profiling of interindividual and interspecies variability in hepatic models. . [Thesis]. Penn State University; 2009. Available from: https://submit-etda.libraries.psu.edu/catalog/9046

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Illinois – Chicago

3. Choi, Su-Young. Hormonal Regulation of Hepatic CYP Expression: Implications in Altered Drug Metabolism during Pregnancy.

Degree: 2012, University of Illinois – Chicago

URL: http://hdl.handle.net/10027/9282

► Pregnancy alters hepatic drug metabolism in a cytochrome P450 (CYP) isoform-specific manner, and rising concentrations of female hormones are potentially responsible for the changes. The… (more)

▼ Pregnancy alters hepatic drug metabolism in a cytochrome P450 (CYP) isoform-specific manner, and rising concentrations of female hormones are potentially responsible for the changes. The objective of this study is to determine the effects of estradiol (E2) and progesterone (PRG) on the expression and activities of hepatic CYPs. In chapter 2, human hepatocytes were treated with E2, PRG, their combination, or known CYP inducers and the mRNA expression and activity levels of CYP were determined. The roles of orphan nuclear receptors in hormone-mediated CYP regulation were also determined by promoter activity assays. The results show that E2 enhances CYP2A6, CYP2B6, and CYP3A4 expression whereas PRG enhances CYP2A6, CYP2B6, CYP2C8, CYP3A4, and CYP3A5 expression. E2 also increased the activities of CYP2C9 and CYP2E1 without affecting the mRNA levels. A combination of estrogens and PRG exhibited an additive effect on CYP3A4 expression, but not on CYP2A6 and CYP2B6 expression. The promoter assays showed that E2 is a constitutive androstane receptor activator, and PRG is a pregnane X receptor activator. When these results were compared with the clinical observations, increased activities of CYP2A6, CYP2C9 and CYP3A4/5 during pregnancy can be, at least in part, attributable to increased female hormone levels. In Chapter 3, we characterized effects of E2 on the expression of rat hepatic CYPs in vivo. Female Sprague-Dawley rats were treated with estradiol benzoate or known CYP inducers, and the expression and activities of CYPs and their modulators were determined. The results showed that E2 enhanced the expression of CYP1A2, CYP2C6, CYP2C7, CYP2C12, and CYP3A9 while the expression of CYP3A1, PXR, CAR, and POR was downregulated. The directional changes observed in female rats are mostly different from those clinically observed during human pregnancy. In chapter 4, we evaluated DMSO-treated Huh 7 cells as an in vitro model system for drug metabolism studies. The results showed that 2% DMSO treatment dramatically induced the mRNA expression levels and activities of most DMEs in Huh7 cells. However, compared to human hepatocytes, the overall expression and activities of DMEs were still low, limiting the utility of DMSO-treated Huh7 cells as a substitution for hepatocytes. Advisors/Committee Members: Jeong, Hyunyoung (advisor), Bolton, Judy (committee member), Burdette, Joanna (committee member), Fischer, James (committee member), van Breemen, Richard (committee member).

Subjects/Keywords: Cytochrome P450; pregnancy; estradiol; progesterone; primary human hepatocytes; drug metabolism

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APA (6^th Edition):

Choi, S. (2012). Hormonal Regulation of Hepatic CYP Expression: Implications in Altered Drug Metabolism during Pregnancy. (Thesis). University of Illinois – Chicago. Retrieved from http://hdl.handle.net/10027/9282

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Choi, Su-Young. “Hormonal Regulation of Hepatic CYP Expression: Implications in Altered Drug Metabolism during Pregnancy.” 2012. Thesis, University of Illinois – Chicago. Accessed January 18, 2021. http://hdl.handle.net/10027/9282.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Choi, Su-Young. “Hormonal Regulation of Hepatic CYP Expression: Implications in Altered Drug Metabolism during Pregnancy.” 2012. Web. 18 Jan 2021.

Vancouver:

Choi S. Hormonal Regulation of Hepatic CYP Expression: Implications in Altered Drug Metabolism during Pregnancy. [Internet] [Thesis]. University of Illinois – Chicago; 2012. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/10027/9282.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Choi S. Hormonal Regulation of Hepatic CYP Expression: Implications in Altered Drug Metabolism during Pregnancy. [Thesis]. University of Illinois – Chicago; 2012. Available from: http://hdl.handle.net/10027/9282

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Universiteit Utrecht

4. Paskel, R.F. Human-Based In Vitro Systems for Predicting In Vivo Hepatic Clearance of Drugs.

Degree: 2013, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/281238

► Unfavorable drug metabolism is the main reason for attrition of new chemical entities and withdrawal of drugs from the market, costing pharmaceutical companies a great… (more)

Subjects/Keywords: in vitro systems; hepatic clearance; in vivo; human; predicting; liver microsomes; liver slices; hepatocytes; primary hepatocytes; HepaRG

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APA (6^th Edition):

Paskel, R. F. (2013). Human-Based In Vitro Systems for Predicting In Vivo Hepatic Clearance of Drugs. (Masters Thesis). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/281238

Chicago Manual of Style (16^th Edition):

Paskel, R F. “Human-Based In Vitro Systems for Predicting In Vivo Hepatic Clearance of Drugs.” 2013. Masters Thesis, Universiteit Utrecht. Accessed January 18, 2021. http://dspace.library.uu.nl:8080/handle/1874/281238.

MLA Handbook (7^th Edition):

Paskel, R F. “Human-Based In Vitro Systems for Predicting In Vivo Hepatic Clearance of Drugs.” 2013. Web. 18 Jan 2021.

Vancouver:

Paskel RF. Human-Based In Vitro Systems for Predicting In Vivo Hepatic Clearance of Drugs. [Internet] [Masters thesis]. Universiteit Utrecht; 2013. [cited 2021 Jan 18]. Available from: http://dspace.library.uu.nl:8080/handle/1874/281238.

Council of Science Editors:

Paskel RF. Human-Based In Vitro Systems for Predicting In Vivo Hepatic Clearance of Drugs. [Masters Thesis]. Universiteit Utrecht; 2013. Available from: http://dspace.library.uu.nl:8080/handle/1874/281238

5. Funakoshi, Natalie. Différenciation des cellules souches embryonnaires humaines vers l'hépatocyte : Production of hepatocytes from human embryonic stem cells.

Degree: Docteur es, Biologie Santé, 2011, Université Montpellier I

URL: http://www.theses.fr/2011MON1T009

►

Les hépatocytes humains adultes en culture primaire (HHCP) ont de nombreuses applications en physiopathologie hépatique, en pharmacologie et en biothérapie, mais sont limitées par leur… (more)

▼

Les hépatocytes humains adultes en culture primaire (HHCP) ont de nombreuses applications en physiopathologie hépatique, en pharmacologie et en biothérapie, mais sont limitées par leur faible disponibilité. Les cellules souches embryonnaires humaines (hES) sont une source prometteuse pour l'obtention d'hépatocytes en grande quantité. Nous avons développé un modèle in vitro de différenciation de hES en hépatocytes en reproduisant toutes les étapes de l'ontogenèse hépatique. Au cours de la différenciation, l'expression de 41 gènes marqueurs du foie a été étudiée et comparée aux HHCP, au foie fœtal et aux progéniteurs hépatiques issus du foie adulte. Les résultats démontrent qu'au bout de 21 jours de différenciation, les cellules souches embryonnaires différenciées en hépatocytes (hES-Hep) ont atteint un état de maturation équivalente aux hépatocytes fœtaux aux alentours de 20 semaines de gestation. L'expression forcée du xénorécepteur CAR dans les hES-Hep a induit l'expression des gènes de la détoxification et la biotransformation de midazolam, un substrat de CYP3A4. Ces résultats pourront contribuer au développement de cultures de hES-Hep comme alternative aux HHCP pour les études du métabolisme des xénobiotiques et pour la thérapie cellulaire.

Primary cultures of human adult hepatocytes (PCHH) have widespread potential applications in liver physiopathology , pharmacology, and cell-based therapies, but are currently limited by poor availability. Human embryonic stem cells (hES) are a promising source for the generation of hepatocytes in large quantities. In this study, we differentiated hES into hepatocytes by mimicking in vitro the various stages of hepatic ontogenesis. We analyzed the expression of a panel of 41 liver marker genes in hepatocyte-like cells derived from hES (hES-Hep) in comparison with PCHH, fetal liver and progenitors obtained from adult liver. The data revealed that after 21 days of differentiation ES-Hep are representative of fetal hepatocytes at around 20 weeks of gestation. The forced expression of the xenoreceptor CAR in hES-Hep induced the expression of detoxification genes as well as the biotransformation of midazolam, a substrate of CYP3A4. These results may contribute to the development of hES-Hep cultures as an alternative to PCHH for studies of xenobiotic metabolism and for cell-based therapies.

Advisors/Committee Members: Maurel, Patrick (thesis director), Gerbal-Chaloin, Sabine (thesis director).

Subjects/Keywords: Cellules souches embryonnaires; Cellules humaines; Hépatocyte; Hepatocytes; Human embryonic stem cells; Human Stem cells

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Funakoshi, N. (2011). Différenciation des cellules souches embryonnaires humaines vers l'hépatocyte : Production of hepatocytes from human embryonic stem cells. (Doctoral Dissertation). Université Montpellier I. Retrieved from http://www.theses.fr/2011MON1T009

Chicago Manual of Style (16^th Edition):

Funakoshi, Natalie. “Différenciation des cellules souches embryonnaires humaines vers l'hépatocyte : Production of hepatocytes from human embryonic stem cells.” 2011. Doctoral Dissertation, Université Montpellier I. Accessed January 18, 2021. http://www.theses.fr/2011MON1T009.

MLA Handbook (7^th Edition):

Funakoshi, Natalie. “Différenciation des cellules souches embryonnaires humaines vers l'hépatocyte : Production of hepatocytes from human embryonic stem cells.” 2011. Web. 18 Jan 2021.

Vancouver:

Funakoshi N. Différenciation des cellules souches embryonnaires humaines vers l'hépatocyte : Production of hepatocytes from human embryonic stem cells. [Internet] [Doctoral dissertation]. Université Montpellier I; 2011. [cited 2021 Jan 18]. Available from: http://www.theses.fr/2011MON1T009.

Council of Science Editors:

Funakoshi N. Différenciation des cellules souches embryonnaires humaines vers l'hépatocyte : Production of hepatocytes from human embryonic stem cells. [Doctoral Dissertation]. Université Montpellier I; 2011. Available from: http://www.theses.fr/2011MON1T009

6. Natarajan, Karthick. Gene networks and transcription factor motifs defining the differentiation of human embryonic stem cells into hepatocyte like cells.

Degree: 2015, Technische Universität Dortmund

URL: http://dx.doi.org/10.17877/DE290R-16518

► In the past decade, it has been recognized that human embryonic stem cells (hESCs) differentiation into hepatocyte like cells (HLCs) could offer an unlimited supply… (more)

▼ In the past decade, it has been recognized that human embryonic stem cells (hESCs) differentiation into hepatocyte like cells (HLCs) could offer an unlimited supply of hepatocytes for pharmacology, toxicology, and cell therapy for liver failure. Many research efforts claimed to have successfully engineered HLCs from hESCs. However, the degree of differentiation and identity of HLCs remains controversial. The primary goal of this thesis work was to obtain a comprehensive understanding of HLCs identity. Thus, HLCs were differentiated from hESCs using a well-established protocol. Genome-wide gene expression programs of hESCs and HLCs were analyzed using GeneChip® Human Genome U133 Plus 2.0 arrays. The resulting gene expression profiles of HLCs and hESCs were compared to freshly isolated adult hepatocytes and adult hepatocytes cultivated for up to 14 days. Application of a broad range of bioinformatic tools and data mining approaches led to elucidation of gene networks and transcription factors (TFs) involved in the regulation of gene expression suggesting successful and failed hepatocyte differentiation. Gene regulatory network analysis revealed that HLCs represent a hybrid cell type with features of the liver, intestine, fibroblast, and stem cells. The undesirable “colon” phenotype was associated with TFs such as KLF5, NKX2-3, as well as CDX2 transcriptional networks. Cluster analysis identified highly correlated groups of genes associated with mature liver functions and downregulated proliferation-associated genes, which approach levels of adult hepatocytes. However, three further clusters failed to reach the gene expression levels of adult hepatocytes. Key TFs of two of these clusters include SOX11, FOXQ1, and YBX3. The third XVI cluster group, controlled by TFs such as HNF1A, CAR, FXR, and PXR, significantly overlaps with genes that are repressed in cultured adult hepatocytes relative to freshly isolated adult hepatocytes, suggesting that the current in vitro conditions lack stimuli essential for maintaining gene expression in hepatocytes, which consequently explains the corresponding functional deficiency of HLCs. In conclusion, the present gene regulatory network approach identified critical transcription factors for interventions to improve differentiation of hESCs to functional maturated hepatocytes. Advisors/Committee Members: Hengstler, Jan Georg (advisor), Sachinidis, Agapios (referee).

Subjects/Keywords: Stem cells; Hepatocyte like cells; Transcription factors; Freshly isolated human hepatocytes; 570; 540

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APA (6^th Edition):

Natarajan, K. (2015). Gene networks and transcription factor motifs defining the differentiation of human embryonic stem cells into hepatocyte like cells. (Doctoral Dissertation). Technische Universität Dortmund. Retrieved from http://dx.doi.org/10.17877/DE290R-16518

Chicago Manual of Style (16^th Edition):

Natarajan, Karthick. “Gene networks and transcription factor motifs defining the differentiation of human embryonic stem cells into hepatocyte like cells.” 2015. Doctoral Dissertation, Technische Universität Dortmund. Accessed January 18, 2021. http://dx.doi.org/10.17877/DE290R-16518.

MLA Handbook (7^th Edition):

Natarajan, Karthick. “Gene networks and transcription factor motifs defining the differentiation of human embryonic stem cells into hepatocyte like cells.” 2015. Web. 18 Jan 2021.

Vancouver:

Natarajan K. Gene networks and transcription factor motifs defining the differentiation of human embryonic stem cells into hepatocyte like cells. [Internet] [Doctoral dissertation]. Technische Universität Dortmund; 2015. [cited 2021 Jan 18]. Available from: http://dx.doi.org/10.17877/DE290R-16518.

Council of Science Editors:

Natarajan K. Gene networks and transcription factor motifs defining the differentiation of human embryonic stem cells into hepatocyte like cells. [Doctoral Dissertation]. Technische Universität Dortmund; 2015. Available from: http://dx.doi.org/10.17877/DE290R-16518

Freie Universität Berlin

7. Józefczuk, Justyna. Die Differenzierung humaner embryonaler Stammzellen in Hepatozyten als eine Methode zur Untersuchung von molekularen Prozessen bei der Hepatogenese in vitro.

Degree: 2010, Freie Universität Berlin

URL: http://dx.doi.org/10.17169/refubium-6032

► Die Differenzierung humaner embryonaler Stammzellen (hESC) in funktionelle Hepatozyten bietet ein effektives in vitro Modellsystem zur Untersuchung von molekularen Mechanismen, die an der Leberentwicklung beteiligt… (more)

▼ Die Differenzierung humaner embryonaler Stammzellen (hESC) in funktionelle Hepatozyten bietet ein effektives in vitro Modellsystem zur Untersuchung von molekularen Mechanismen, die an der Leberentwicklung beteiligt sind. Darüber hinaus kann die gut charakterisierte, erneuerbare, aus humanen ES-Zellen differenzierte Hepatozytenquelle für in vitro Tests verwendet werden, welche die Verstoffwechselung von Pharmaka untersuchen, sowie in der Toxikologie. Mechanismen der zugrunde liegenden molekular-embryologischen Prozesse, die zu der fötalen Leberentwicklung führen, wurden in der Vergangenheit mittels genetischer Analysen in Nagetieren sowie durch Explantatstudien an Modellorganismen wie Hühnerembryonen untersucht. Die pluripotenten Eigenschaften der embryonalen Stammzellen eröffnen heutzutage diverse Möglichkeiten zur Erforschung der Frühentwicklung des Menschen. Unter anderem stehen Protokolle zur Verfügung die die Differenzierung von humanen ES-Zellen in Zellen mit typischen morphologischen und molekularen Hepatozytenmerkmalen ermöglichen. Durch genetische Studien an Modellorganismen wurden die wichtigsten Induktoren der Hepatogenese wie FGF4, BMP2, HGF sowie Oncostatin M und Dexamethason aufgedeckt. Die derzeit gröβte Herausforderung ist es, deren leberspezifische Zielgene zu identifizieren und einen Einblick in den jeweiligen Induktionsprozess zu gewinnen. Solche Induktionsprozesse werden durch extrazelluläre Liganden reguliert, welche gewöhnlich während des in vitro Differenzierungsprozesses hinzugefügt werden. Dieses Wissen erweitert wiederum unser Verständnis der dynamischen Entwicklungsprozesse auf der Transkriptions- und Proteomebene. Das Ziel dieser Studie war es, in vitro Hepatogenesemechanismem aufzuklären, die den Prozess imitieren, welcher in vivo abläuft. Um die zeitliche Abfolge der differenziellen Genxpression im Prozess der Hepatogenese zu untersuchen, verwendete ich ein reproduzierbares in vitro System (zwei verschiedene Protokolle) und untersuchte schrittweise die Transkriptome verschiedener Differenzierungsstadien der humanen ES-Zellen: endgültig induziertes Entoderm, frühe Leberzellen, adulte Leberzellen. Diese in vitro Analysen haben ein breites Spektrum molekularer Kaskaden aufgedeckt, in die Oberflächenrezeptoren, Transkriptionsregulatoren sowie intrazelluläre Systeme der Signalübertragung involviert sind und welche für die Induktion der Hepatogenese in vivo verantwortlich sein könnten. Darüber hinaus haben die Experimente gezeigt, dass die Hepatozyten-ähnlichen Zellen, die aus undifferenzierten hES-Zellen generiert wurden, auf der Transkriptionsebene eine ähnliche Genaktivität aufweisen wie die Zellen der fötalen Leber. Advisors/Committee Members: n (gender), Prof. Dr. Hans Lehrach (firstReferee), Prof. Dr. Petra Knaus (furtherReferee).

Subjects/Keywords: human Embryonic Stem Cells; hepatocytes; expression profilling; 500 Naturwissenschaften und Mathematik::570 Biowissenschaften; Biologie

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APA (6^th Edition):

Józefczuk, J. (2010). Die Differenzierung humaner embryonaler Stammzellen in Hepatozyten als eine Methode zur Untersuchung von molekularen Prozessen bei der Hepatogenese in vitro. (Thesis). Freie Universität Berlin. Retrieved from http://dx.doi.org/10.17169/refubium-6032

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Józefczuk, Justyna. “Die Differenzierung humaner embryonaler Stammzellen in Hepatozyten als eine Methode zur Untersuchung von molekularen Prozessen bei der Hepatogenese in vitro.” 2010. Thesis, Freie Universität Berlin. Accessed January 18, 2021. http://dx.doi.org/10.17169/refubium-6032.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Józefczuk, Justyna. “Die Differenzierung humaner embryonaler Stammzellen in Hepatozyten als eine Methode zur Untersuchung von molekularen Prozessen bei der Hepatogenese in vitro.” 2010. Web. 18 Jan 2021.

Vancouver:

Józefczuk J. Die Differenzierung humaner embryonaler Stammzellen in Hepatozyten als eine Methode zur Untersuchung von molekularen Prozessen bei der Hepatogenese in vitro. [Internet] [Thesis]. Freie Universität Berlin; 2010. [cited 2021 Jan 18]. Available from: http://dx.doi.org/10.17169/refubium-6032.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Józefczuk J. Die Differenzierung humaner embryonaler Stammzellen in Hepatozyten als eine Methode zur Untersuchung von molekularen Prozessen bei der Hepatogenese in vitro. [Thesis]. Freie Universität Berlin; 2010. Available from: http://dx.doi.org/10.17169/refubium-6032

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Freie Universität Berlin

8. Morgül, Mehmet Haluk. Iron-oxide labelling of primary human hepatocytes for detection via magnet resonance imaging.

Degree: 2010, Freie Universität Berlin

URL: http://dx.doi.org/10.17169/refubium-10158

► Transplantation of primary human hepatocytes is a promising approach in certain liver diseases. For visualisation of hepatocytes during and following cell application and the ability… (more)

▼ Transplantation of primary human hepatocytes is a promising approach in certain liver diseases. For visualisation of hepatocytes during and following cell application and the ability of a timely response to potential complications, a non-invasive modality for imaging of the transplanted cells has to be established. Magnetic resonance imaging (MRI) could enable real-time tracking and long-term detection of transplanted hepatocytes. The use of superparamagnetic iron oxide particles as cellular contrast agents should allow for the non-invasive detection of labelled cells on high-resolution magnetic resonance images. In this study, experiments were performed on primary human hepatocytes to transfer the method of detecting labelled cells via clinical MRI into human hepatocyte transplantation. Furthermore, a method for preparation of labelled primary human hepatocytes is developed - The cells were isolated, labelled and enzymaticaly resuspended. The effects of these manipulations were determined via standardised culture parameters in vitro. After the incubation of the hepatocytes with tat-modified nano-meter sized “superparamagteic iron oxide particles, and “micron sized iron oxide particles” for one hour and four hours, respectively, the incorporation or particles were determined via microscopy. The phantom samples of labelled cells showed typical hypointensity in T2*-weighted MRI. The particle load was not affected by resuspension and showed no alternations during the culture period. Compared to control groups, labelling and resuspension had no adverse effects on viability, enzyme leakage and metabolic activity of human hepatocytes. This present study describes a new method for labelling of primary human hepatocytes for their detection via clinical MRI equipment. Furthermore, it shows a novel procedure, which serves for basic research and quality control in the clinical setting of human hepatocyte transplantation. Advisors/Committee Members: [email protected] (contact), m (gender), Priv.-Doz. Dr. med. I. M. Sauer (firstReferee), Prof. Dr. med. S. Jonas, Priv.-Doz. Dr. med. U. Teichgräber (furtherReferee).

Subjects/Keywords: MRI; transplantation; human hepatocytes; 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Morgül, M. H. (2010). Iron-oxide labelling of primary human hepatocytes for detection via magnet resonance imaging. (Thesis). Freie Universität Berlin. Retrieved from http://dx.doi.org/10.17169/refubium-10158

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Morgül, Mehmet Haluk. “Iron-oxide labelling of primary human hepatocytes for detection via magnet resonance imaging.” 2010. Thesis, Freie Universität Berlin. Accessed January 18, 2021. http://dx.doi.org/10.17169/refubium-10158.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Morgül, Mehmet Haluk. “Iron-oxide labelling of primary human hepatocytes for detection via magnet resonance imaging.” 2010. Web. 18 Jan 2021.

Vancouver:

Morgül MH. Iron-oxide labelling of primary human hepatocytes for detection via magnet resonance imaging. [Internet] [Thesis]. Freie Universität Berlin; 2010. [cited 2021 Jan 18]. Available from: http://dx.doi.org/10.17169/refubium-10158.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Morgül MH. Iron-oxide labelling of primary human hepatocytes for detection via magnet resonance imaging. [Thesis]. Freie Universität Berlin; 2010. Available from: http://dx.doi.org/10.17169/refubium-10158

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Illinois – Chicago

9. Ferrari, Erika. Optimized Protein Patterning Methods for Human Liver Cultures.

Degree: 2018, University of Illinois – Chicago

URL: http://hdl.handle.net/10027/23105

► Organizing cells on extracellular matrix (ECM) proteins is useful for optimizing cell-cell interactions and therefore cell functions in vitro. In the case of the liver,… (more)

▼ Organizing cells on extracellular matrix (ECM) proteins is useful for optimizing cell-cell interactions and therefore cell functions in vitro. In the case of the liver, micropatterned co-cultures (MPCCs) containing primary human hepatocytes (PHHs) and 3T3-J2 murine embryonic fibroblasts adhered to hard surfaces (e.g. glass and plastic) have been shown to exhibit high levels of hepatic functions for several weeks in vitro; the use of PHHs in this model mitigates the differences observed in drug metabolism enzymatic pathways between animal (e.g. rodents) and human livers. Furthermore, MPCCs have been previously augmented with liver sinusoidal endothelial cells (LSECs) or human umbilical vein endothelial cell (HUVECs) non-liver controls to model the interactions between PHHs and endothelial cells as in vivo; however, this study was limited to gene expression analysis of the endothelial phenotype, which may not correlate with functional markers. This thesis seeks to build upon the MPCC platform to a) develop and optimize an alternative technique than currently used for patterning proteins onto softer surfaces that more accurately mimic the stiffness of the liver, and b) determine protein marker expression of the endothelial cells in monocultures and co-cultures with PHHs and/or fibroblasts to complement the published gene expression data set. Towards the first aim, we optimized parameters for a soft lithographic microcontact protein printing method using polydimethylsiloxane (PDMS) stamps and subsequently showed its utility for the creation of highly functional MPCCs on both collagen and fibronectin stamped domains on glass. Additional studies demonstrated the utility of this method for patterning proteins and cells on softer surfaces in the kPa range of stiffness as opposed to the GPa range of stiffness for glass and plastic. Towards the second aim of this thesis, we tested three protein markers (CD31, SE-1, and Factor VIII) for their ability to distinguish LSECs and HUVECs in pure cultures, co-cultures with either PHHs or fibroblasts, and tri-cultures containing endothelial cells, PHHs, and fibroblasts. Our results showed that while CD31 (immunostaining) and Factor VIII secretion (as assessed via enzyme linked immunosorbent assay) were detected in both endothelial cell types, SE-1 could distinguish LSECs from HUVECs, but only in pure monocultures reliably since this marker was downregulated in co-/tri-cultures containing LSECs, cross-reacted with mouse fibroblast protein(s), and showed upregulation in HUVECs in co-culture with PHHs. Overall, our studies set the stage for the creation and phenotypic characterization of multicellular human liver models on surfaces that mimic liver-like stiffness, which will have robust utility for drug screening and ultimately, regenerative medicine. Advisors/Committee Members: Khetani, Salman R (advisor), Eddington, David (committee member), Rasponi, Marco (committee member), Khetani, Salman R (chair).

Subjects/Keywords: MPCC (micropatterned co-cultures); PHHs (primary human hepatocytes); LSECs (liver sinusoidal endothelial cells

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ferrari, E. (2018). Optimized Protein Patterning Methods for Human Liver Cultures. (Thesis). University of Illinois – Chicago. Retrieved from http://hdl.handle.net/10027/23105

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Ferrari, Erika. “Optimized Protein Patterning Methods for Human Liver Cultures.” 2018. Thesis, University of Illinois – Chicago. Accessed January 18, 2021. http://hdl.handle.net/10027/23105.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Ferrari, Erika. “Optimized Protein Patterning Methods for Human Liver Cultures.” 2018. Web. 18 Jan 2021.

Vancouver:

Ferrari E. Optimized Protein Patterning Methods for Human Liver Cultures. [Internet] [Thesis]. University of Illinois – Chicago; 2018. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/10027/23105.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Ferrari E. Optimized Protein Patterning Methods for Human Liver Cultures. [Thesis]. University of Illinois – Chicago; 2018. Available from: http://hdl.handle.net/10027/23105

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Kansas

10. Kazmi, Faraz. SYSTEM-DEPENDENT METABOLISM OF DRUGS BY CYTOCHROME P450: THE MECHANISTIC BASIS FOR WHY HUMAN LIVER MICROSOMES ARE SUPERIOR TO HUMAN HEPATOCYTES AT METABOLIZING MIDAZOLAM BUT INFERIOR AT METABOLIZING DESLORATADINE.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2015, University of Kansas

URL: http://hdl.handle.net/1808/19448

► In the pharmaceutical industry, pooled human liver microsomes (HLM) and pooled cryopreserved human hepatocytes (CHH) are the most commonly used test systems to measure the… (more)

▼ In the pharmaceutical industry, pooled human liver microsomes (HLM) and pooled cryopreserved human hepatocytes (CHH) are the most commonly used test systems to measure the in vitro metabolic intrinsic clearance (CLint) of investigational new drugs in order to identify drug candidates with favorable pharmacokinetic properties such as once-a-day dosing and low oral dose. However, both HLM and CHH have been shown to underpredict the in vivo clearance of drugs. For drugs whose clearance is predominantly determined by P450 enzymes, metabolic clearance in CHH would be expected to equal that in HLM even if both test systems underpredicted (or overpredicted) in vivo clearance. Curiously, in the case of drugs with high intrinsic clearance (CLint), CHH underpredict in vivo clearance to a greater extent than HLM. Such system-dependent clearance has been reported for midazolam, a high CLint drug that is the most widely used CYP3A4/5 substrate for both the in vitro and in vivo assessment of drug-drug interactions (DDIs). Previous investigators have proposed that the system-dependent clearance of midazolam is due to permeability- or cofactor-restricted clearance in CHH (i.e., clearance in hepatocytes is limited by membrane permeability or the availability of NADPH). The objective of this dissertation research was to determine the mechanism underlying the system-dependent clearance of midazolam. Studies of midazolam clearance in HLM and CHH confirmed previous reports that midazolam clearance is almost an order of magnitude lower in CHH than HLM, a system-dependent difference that was much more pronounced than with other CYP3A4/5 substrates (namely alfentanil, nifedipine and verapamil). In vitro to in vivo extrapolation (IVIVE) of clearance established that HLM accurately predicted the in vivo clearance of midazolam whereas CHH underpredicted midazolam clearance by a factor of 5. Permeabilizing CHH by sonication or treatment with the pore-forming agent saponin did not increase the rate of midazolam metabolism, even in the presence of excess NADPH. Furthermore, the rate of midazolam uptake by CHH was found to greatly exceed the rate of midazolam metabolism, and microsomes isolated from pooled CHH had comparable CYP3A4/5 activity towards midazolam as microsomes prepared directly from human liver. These results suggested that neither membrane permeability nor intracellular cofactor availability were likely explanations for the system-dependent clearance of midazolam. The impact of in vitro incubation conditions on P450 activity, namely the ionic strength of the incubation buffer and the effect of cell culture media, was evaluated as a possible explanation for the system-dependent clearance of midazolam. As part of this investigation, a cell culture medium was sought that was capable of increasing midazolam clearance in CHH. Compared with KHB (the medium used in the initial experiment), Williams’ E medium supported similar rates of midazolam metabolism but the other three media examined, namely Waymouth’s, MCM+ and DMEM, supported lower… Advisors/Committee Members: Parkinson, Andrew (advisor), Reed, Gregory (advisor), Weir, Scott (cmtemember), Lampe, Jed (cmtemember), Krise, Jeffrey (cmtemember).

Subjects/Keywords: Toxicology; Pharmaceutical sciences; Pharmacology; Cytochrome P450; Drug-drug interactions; Drug Metabolism; Human hepatocytes; Human liver microsomes; Uridine Glucuronosyltransferase

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Kazmi, F. (2015). SYSTEM-DEPENDENT METABOLISM OF DRUGS BY CYTOCHROME P450: THE MECHANISTIC BASIS FOR WHY HUMAN LIVER MICROSOMES ARE SUPERIOR TO HUMAN HEPATOCYTES AT METABOLIZING MIDAZOLAM BUT INFERIOR AT METABOLIZING DESLORATADINE. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/19448

Chicago Manual of Style (16^th Edition):

Kazmi, Faraz. “SYSTEM-DEPENDENT METABOLISM OF DRUGS BY CYTOCHROME P450: THE MECHANISTIC BASIS FOR WHY HUMAN LIVER MICROSOMES ARE SUPERIOR TO HUMAN HEPATOCYTES AT METABOLIZING MIDAZOLAM BUT INFERIOR AT METABOLIZING DESLORATADINE.” 2015. Doctoral Dissertation, University of Kansas. Accessed January 18, 2021. http://hdl.handle.net/1808/19448.

MLA Handbook (7^th Edition):

Kazmi, Faraz. “SYSTEM-DEPENDENT METABOLISM OF DRUGS BY CYTOCHROME P450: THE MECHANISTIC BASIS FOR WHY HUMAN LIVER MICROSOMES ARE SUPERIOR TO HUMAN HEPATOCYTES AT METABOLIZING MIDAZOLAM BUT INFERIOR AT METABOLIZING DESLORATADINE.” 2015. Web. 18 Jan 2021.

Vancouver:

Kazmi F. SYSTEM-DEPENDENT METABOLISM OF DRUGS BY CYTOCHROME P450: THE MECHANISTIC BASIS FOR WHY HUMAN LIVER MICROSOMES ARE SUPERIOR TO HUMAN HEPATOCYTES AT METABOLIZING MIDAZOLAM BUT INFERIOR AT METABOLIZING DESLORATADINE. [Internet] [Doctoral dissertation]. University of Kansas; 2015. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/1808/19448.

Council of Science Editors:

Kazmi F. SYSTEM-DEPENDENT METABOLISM OF DRUGS BY CYTOCHROME P450: THE MECHANISTIC BASIS FOR WHY HUMAN LIVER MICROSOMES ARE SUPERIOR TO HUMAN HEPATOCYTES AT METABOLIZING MIDAZOLAM BUT INFERIOR AT METABOLIZING DESLORATADINE. [Doctoral Dissertation]. University of Kansas; 2015. Available from: http://hdl.handle.net/1808/19448

11. Ndongo Thiam, Ndiémé. Etude de la réponse humorale neutralisante contre le Virus de l’Hépatite C : Study of the neutralizing antibody response against the hepatitis C virus.

Degree: Docteur es, Biologie moléculaire intégrative et cellulaire, 2010, Université Claude Bernard – Lyon I

URL: http://www.theses.fr/2010LYO10019

►

Le virus de l’hépatite C (HCV) est l’agent responsable de l’hépatite C, maladie qui touche environ 3% de lapopulation mondiale. Une des caractéristiques de cette… (more)

▼

Le virus de l’hépatite C (HCV) est l’agent responsable de l’hépatite C, maladie qui touche environ 3% de lapopulation mondiale. Une des caractéristiques de cette infection est son évolution dans 60 à 90% des casvers des formes chroniques avec des complications sévères telles que la cirrhose et le carcinomehépatocellulaire. Un des handicaps majeurs de la recherche sur le HCV est l’absence de systèmes decultures in vitro efficaces et de modèles animaux adaptés car le HCV n’infecte que l’homme et le chimpanzé.l’anticorps D32.10. Pour cela, nous avons développé un test de cellbindinget nous avons montré quel’interaction des particules virales sériques (HCVsp) radiomarquées à l’Iode 125 avec les celluleshépatocytaires (Huh‐7 et HepaRG) est spécifique et saturable impliquant des sites de haute et faible affinité.De plus, l’anticorps D32.10 est capable d’inhiber spécifiquement et efficacement les interactions de hauteaffinité entre les HCVsp et les cellules HepaRG avec une IC50 ≤ 0,5 μg/ml. Nous avons mis en évidence quel’inhibition est plus efficace lorsque nous utilisons sélectivement une population de particules HCVenveloppées exprimant fortement E1E2. Récemment, nous avons développé un système d’infection originaldes cellules HepaRG qui sont des cellules progénitrices du foie par les HCVsp et avons montré quel’infection, la réplication et la propagation dépendent de l’état de prolifération/différenciation de cescellules. Nous avons aussi démontré que les particules virales produites dans ce système contiennent del’ARN viral, expriment les protéines d’enveloppe E1E2 et sont infectieuses. Des études préliminairesmontrent que l’anticorps D32.10 inhibe fortement l’infection (95% à 80% aux jours 14 et 21 aprèsinfection) vraisemblablement au niveau des étapes précoces du cycle viral.Dans un second temps, nous avons recherché la prévalence des anticorps de même spécificité que le D32.10(anti‐E1E2A,B) dans différents groupes de patients HCV positifs afin de déterminer leur significationbiologique. Par un test ELISA utilisant les peptides biotinylés E1, E2A et E2B dans la phase de capture, nousavons démontré que la réponse anticorps anti‐E1E2A,B était présente dans 90% des cas chez les patientsqui guérissent spontanément avec des titres élevées (≥ 1/1000). Cette réponse humorale est absente ourare (< 10%) chez les patients porteurs chroniques non traités ou non répondeurs aux traitementsantiviraux. Une étude longitudinale a été réalisée chez des patients non répondeurs ou répondeursdéveloppant une réponse virologique soutenue à une bithérapie standard, interféron pégylé plus ribavirine.L’analyse statistique des résultats a montré que les anticorps anti‐E1E2A,B pouvaient être prédictifs de laréponse au traitement avec une spécificité et une valeur prédictive positive de 100%.La convergence des résultats in vitro et in vivo supporte un rôle neutralisant de l’anticorps monoclonalD32.10, permettant d’envisager son utilisation en immunothérapie.

Hepatitis C Virus (HCV) is the major etiological agent of liver disease in the world…

Advisors/Committee Members: Petit, Marie-Anne (thesis director).

Subjects/Keywords: Virus de l’hépatite C; Glycoprotéines d’enveloppe; Anticorps monoclonal; Neutralisation; Cellules hépatocytaires; Hepatitis C virus; Envelope glycoproteins; Monoclonal antibody; Neutralisation; Human hepatocytes

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ndongo Thiam, N. (2010). Etude de la réponse humorale neutralisante contre le Virus de l’Hépatite C : Study of the neutralizing antibody response against the hepatitis C virus. (Doctoral Dissertation). Université Claude Bernard – Lyon I. Retrieved from http://www.theses.fr/2010LYO10019

Chicago Manual of Style (16^th Edition):

Ndongo Thiam, Ndiémé. “Etude de la réponse humorale neutralisante contre le Virus de l’Hépatite C : Study of the neutralizing antibody response against the hepatitis C virus.” 2010. Doctoral Dissertation, Université Claude Bernard – Lyon I. Accessed January 18, 2021. http://www.theses.fr/2010LYO10019.

MLA Handbook (7^th Edition):

Ndongo Thiam, Ndiémé. “Etude de la réponse humorale neutralisante contre le Virus de l’Hépatite C : Study of the neutralizing antibody response against the hepatitis C virus.” 2010. Web. 18 Jan 2021.

Vancouver:

Ndongo Thiam N. Etude de la réponse humorale neutralisante contre le Virus de l’Hépatite C : Study of the neutralizing antibody response against the hepatitis C virus. [Internet] [Doctoral dissertation]. Université Claude Bernard – Lyon I; 2010. [cited 2021 Jan 18]. Available from: http://www.theses.fr/2010LYO10019.

Council of Science Editors:

Ndongo Thiam N. Etude de la réponse humorale neutralisante contre le Virus de l’Hépatite C : Study of the neutralizing antibody response against the hepatitis C virus. [Doctoral Dissertation]. Université Claude Bernard – Lyon I; 2010. Available from: http://www.theses.fr/2010LYO10019

12. 남, 가은. Abrogation of B-RafV600E induced senescence by AKT activation via FoxM1 expression in primary human hepatocytes.

Degree: 2017, Ajou University

URL: http://repository.ajou.ac.kr/handle/201003/16430 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000024361

►

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. Hepatocarcinogenesis is a stepwise process and multiple genes alteration are involved… (more)

▼

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. Hepatocarcinogenesis is a stepwise process and multiple genes alteration are involved such as activation of oncogenes, inactivation of tumor suppressor genes, activation of growth factor and their cognitive receptors, reactivation of developmental pathways and activation of cell cycle regulator. In general, MAPK and the PIK3CA signalling pathways have a key role in cell proliferation and survival and their oncogenic activation deeply contributes to pathogenesis of different solid tumors. B-Raf mutation has been reported in 61% of melanoma, 53% of papillary thyroid cancer and 11.5% of colorectal cancer patients. In case of hepatoma, 23% of B-RafV600E mutation has been reported. Furthermore, PI3K pathway activation was found about 40% of HCC cases. Therefore, in this study, we evaluated the role of B-RafV600E and PI3K pathway signaling in hepatocarcinogenesis. Overexpression of B-RafV600E in primary human hepatocytes caused cell growth arrest and increased senescence-associated beta-galactosidase (SA-β-gal) staining. Furthermore, we found that shPTEN induced cellular senescence. We further investigated that shPTEN and B-RafV600E co-infection effect in hepatocarcinogenesis and found that overcome of senescence was observed. At the mechanism level, B-RafV600E infection decreased FoxM1 expression. However, co-infection increased FoxM1 expression. Furthermore, B-RafV600E and FoxM1 co-infected hepatocytes also showed overcome of B-RafV600E induced senescence.

유전자의 변형이 발생하는데 크게 발암유전자의 활성, 발암억제유전자의 비활성화, 발달과정에 관여하는 신호전달경로의 재활성, 성장인자와 그 수용체의 활성화, 전사인자의 활성으로 나뉘게 된다. 일반적으로는 MAPK와 PIK3CA 신호전달경로가 세포증식과 성장에 중요한 핵심이 되며 이 경로에 관여하는 여러 가지 발암유전자 활성이 간세포암 뿐만 아니라 다양한 고형암에 기여하는 것으로 알려져 있으며, 세포 증식과 성장 그리고 간암세포의 전이에 관여하는 MAPK 신호전달 경로에 대한 연구를 진행하였다. MAPK 경로에 포함되는 발암유전자인 B-Raf 돌연변이는 흑색종에서 61%, 갑상선암에서 53%, 대장암에서 11.5%로 각각 보고 되었으며 또한 간세포암에서는 B-RafV600E 돌연변이가 23% 보고되어 있으며, 간암발생과정에 있어서 B-RafV600E의 역할에 대해 알아보고자 하였다. B-RafV600E를 인간 일차 간세포에 과발현시켰더니 세포성장이 멈추었고 SA-β-gal 염색의 비율이 증가함으로써 노화 현상을 관찰하였다. 다음으로 간세포암에서 PTEN의 발현이 ~40%정도 감소되어있어 인간 일차 간세포에 PTEN의 발현을 감소시켰더니 이 또한 노화가 나타나는 결과를 관찰하였고 다음으로는 PTEN의 발현 감소와 함께 B-RrafV600E를 인간 일차 간세포에 발현시켰더니 노화가 극복되는 결과를 관찰하였다. 더불어, 앞서 B-RafV600E에 의해 유도된 노화세포에서 FoxM1의 발현이 감소되는것을 확인하였는데 B-RafV600E와 FoxM1을 같이 인간 일차 간세포에 발현시켜보았더니 이 또한 노화가 극복되는 양상을 관찰할 수 있었다. 본 연구에서는 인간 일차 간세포를 이용하여 간암발생과정에 대한 기전을 밝히고자 하였으며 이를 토대로 간암환자를 위한 치료에 기여할 것이라고 예상하는바이다.

I. INTRODUCTION 1 II. MATERIALS AND METHODS 4 1. Cell line and Culture conditions 4 2. Plasmids and Lentivirus Preparation 4 3. RNA interference 4 4. Immunoblotting 5 5. Quantitative Realtime RT–PCR 5 6. SenescenceAssociated βGalactosidase staining 6 7. Soft agar colony forming assay 6 8. Statistical Analysis 6 III. RESULTS 7 1. BRafV600E induced senescence in primary human hepatocytes. 7 2. Downregulation of PTEN in primary human hepatocytes induced senescence. 14 3. Senescence induced by BRafV600E can be overcome with shPTEN co infection. 18 4. BRafV600E and FoxM1 coinfected…

Advisors/Committee Members: 대학원 의생명과학과, 201424576, 남, 가은.

Subjects/Keywords: Hepatocellular carcinoma; HCC; Hepatocarcinogenesis; Primary human hepatocytes; B-RafV600E; PTEN; FoxM1; 간세포암; 간암발생과정; 인간일차간세포; B-RafV600E; MAPK; PTEN; FoxM1

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

남, �. (2017). Abrogation of B-RafV600E induced senescence by AKT activation via FoxM1 expression in primary human hepatocytes. (Thesis). Ajou University. Retrieved from http://repository.ajou.ac.kr/handle/201003/16430 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000024361

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

남, 가은. “Abrogation of B-RafV600E induced senescence by AKT activation via FoxM1 expression in primary human hepatocytes.” 2017. Thesis, Ajou University. Accessed January 18, 2021. http://repository.ajou.ac.kr/handle/201003/16430 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000024361.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

남, 가은. “Abrogation of B-RafV600E induced senescence by AKT activation via FoxM1 expression in primary human hepatocytes.” 2017. Web. 18 Jan 2021.

Vancouver:

남 �. Abrogation of B-RafV600E induced senescence by AKT activation via FoxM1 expression in primary human hepatocytes. [Internet] [Thesis]. Ajou University; 2017. [cited 2021 Jan 18]. Available from: http://repository.ajou.ac.kr/handle/201003/16430 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000024361.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

남 �. Abrogation of B-RafV600E induced senescence by AKT activation via FoxM1 expression in primary human hepatocytes. [Thesis]. Ajou University; 2017. Available from: http://repository.ajou.ac.kr/handle/201003/16430 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000024361

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Freie Universität Berlin

13. Lübberstedt, Marc. Optimisation of pharmacological studies on hepatic cells in 2D and 3D cultures.

Degree: 2015, Freie Universität Berlin

URL: http://dx.doi.org/10.17169/refubium-10768

► The liver is a central organ for biotransformation and detoxification of endogenous and xenobiotic substances and plays a major role in research on pharmacokinetics and… (more)

Subjects/Keywords: 3D culture; primary human hepatocytes; bioreactor; CYP; 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Lübberstedt, M. (2015). Optimisation of pharmacological studies on hepatic cells in 2D and 3D cultures. (Thesis). Freie Universität Berlin. Retrieved from http://dx.doi.org/10.17169/refubium-10768

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Lübberstedt, Marc. “Optimisation of pharmacological studies on hepatic cells in 2D and 3D cultures.” 2015. Thesis, Freie Universität Berlin. Accessed January 18, 2021. http://dx.doi.org/10.17169/refubium-10768.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Lübberstedt, Marc. “Optimisation of pharmacological studies on hepatic cells in 2D and 3D cultures.” 2015. Web. 18 Jan 2021.

Vancouver:

Lübberstedt M. Optimisation of pharmacological studies on hepatic cells in 2D and 3D cultures. [Internet] [Thesis]. Freie Universität Berlin; 2015. [cited 2021 Jan 18]. Available from: http://dx.doi.org/10.17169/refubium-10768.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Lübberstedt M. Optimisation of pharmacological studies on hepatic cells in 2D and 3D cultures. [Thesis]. Freie Universität Berlin; 2015. Available from: http://dx.doi.org/10.17169/refubium-10768

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Freie Universität Berlin

14. Pfeiffer, Elisa. Isolation, characterization and cultivation of human hepatocytes and non- parenchymal liver cells for pharmacological investigations.

Degree: 2017, Freie Universität Berlin

URL: http://dx.doi.org/10.17169/refubium-14213

► Use of primary human hepatocytes (PHH) is considered to be the gold standard for the in vitro study of drug metabolism and hepatotoxicity. PHH monocultures… (more)

▼ Use of primary human hepatocytes (PHH) is considered to be the gold standard for the in vitro study of drug metabolism and hepatotoxicity. PHH monocultures are quite limited in its life and functionality. Complex mechanisms of action can only be displayed insufficiently. Hepatic non-parenchymal cells (NPC) as Kupffer cells (KC), liver endothelial cells (LEC) and hepatic stellate cells (HSC) play a central role in maintaining the PHH functions, as well as in regenerative and pathophysiological processes of the liver. To develop functional and reproducible in vitro liver models, the availability of parenchymal and non-parenchymal liver cells in a defined quality and quantity is essential. The aim of the present study was to establish a protocol for the parallel isolation of human PHH and NPC from the liver tissue of one donor, and the study of cell-specific properties for a potential use of those cells in in vitro liver systems. Human PHH and NPC were isolated from healthy liver tissue following partial hepatectomy by a two - step EDTA / collagenase perfusion technique. The obtained cell fractions were purified by a Percoll density gradient centrifugation and separated by specific adherence properties and a magnetically activated cell sorting (MACS®). KC, LEC and HSC were identified and cultured in monocultures. Using cell-type specific properties the behavior and stability of NPC were characterized in culture. Per gram of liver tissue there was a yield of 1.9 x 106 KC, 2.7 x 105 LEC and 4.7 x 105 HSC achieved, with a viability of > 90%. Functional characterization of NPC showed an activation of all populations in culture. Activation of the KC, coupled with a strong lost of viability was registered within 4 - 5 days. LEC lost in culture cell-specific characteristics, while HSC underwent a process of transformation into a myofibroblastlike cell type. The study of different culture conditions for HSC showed that the dedifferentiation of the cells was attenuated in vitro, but could not be completely prevented. The procedure described allows the simultaneous isolation and separation of human PHH and NPC in a high quality and yield. Advisors/Committee Members: w (gender), N.N. (firstReferee), N.N. (furtherReferee).

Subjects/Keywords: primary human hepatocytes; non-parenchymal liver cells; isolation; 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Pfeiffer, E. (2017). Isolation, characterization and cultivation of human hepatocytes and non- parenchymal liver cells for pharmacological investigations. (Thesis). Freie Universität Berlin. Retrieved from http://dx.doi.org/10.17169/refubium-14213

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Pfeiffer, Elisa. “Isolation, characterization and cultivation of human hepatocytes and non- parenchymal liver cells for pharmacological investigations.” 2017. Thesis, Freie Universität Berlin. Accessed January 18, 2021. http://dx.doi.org/10.17169/refubium-14213.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Pfeiffer, Elisa. “Isolation, characterization and cultivation of human hepatocytes and non- parenchymal liver cells for pharmacological investigations.” 2017. Web. 18 Jan 2021.

Vancouver:

Pfeiffer E. Isolation, characterization and cultivation of human hepatocytes and non- parenchymal liver cells for pharmacological investigations. [Internet] [Thesis]. Freie Universität Berlin; 2017. [cited 2021 Jan 18]. Available from: http://dx.doi.org/10.17169/refubium-14213.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Pfeiffer E. Isolation, characterization and cultivation of human hepatocytes and non- parenchymal liver cells for pharmacological investigations. [Thesis]. Freie Universität Berlin; 2017. Available from: http://dx.doi.org/10.17169/refubium-14213

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

15. LIM LAY KENG. The Mechanistic Role of Mitochondrial Oxidative stress in Troglitazone - Induced Apoptosis in Human Hepatocytes.

Degree: 2008, National University of Singapore

URL: http://scholarbank.nus.edu.sg/handle/10635/16083

Subjects/Keywords: hepatotoxicity; mitochondria; oxidative stress; troglitazone; human hepatocytes; apoptosis

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

KENG, L. L. (2008). The Mechanistic Role of Mitochondrial Oxidative stress in Troglitazone - Induced Apoptosis in Human Hepatocytes. (Thesis). National University of Singapore. Retrieved from http://scholarbank.nus.edu.sg/handle/10635/16083

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

KENG, LIM LAY. “The Mechanistic Role of Mitochondrial Oxidative stress in Troglitazone - Induced Apoptosis in Human Hepatocytes.” 2008. Thesis, National University of Singapore. Accessed January 18, 2021. http://scholarbank.nus.edu.sg/handle/10635/16083.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

KENG, LIM LAY. “The Mechanistic Role of Mitochondrial Oxidative stress in Troglitazone - Induced Apoptosis in Human Hepatocytes.” 2008. Web. 18 Jan 2021.

Vancouver:

KENG LL. The Mechanistic Role of Mitochondrial Oxidative stress in Troglitazone - Induced Apoptosis in Human Hepatocytes. [Internet] [Thesis]. National University of Singapore; 2008. [cited 2021 Jan 18]. Available from: http://scholarbank.nus.edu.sg/handle/10635/16083.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

KENG LL. The Mechanistic Role of Mitochondrial Oxidative stress in Troglitazone - Induced Apoptosis in Human Hepatocytes. [Thesis]. National University of Singapore; 2008. Available from: http://scholarbank.nus.edu.sg/handle/10635/16083

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Florida

16. Frock, Adam. Utilizing Decellularized Porcine Liver Matrix as a Platform for 3-Dimensional Hepatic Cell Culture.

Degree: MS, Medical Sciences - Medicine, 2014, University of Florida

URL: https://ufdc.ufl.edu/UFE0047605

► The liver is responsible for numerous functions critical to maintaining homeostasis of the body, thus hepatic injury often results in mortality if an orthotropic transplant… (more)

Subjects/Keywords: Cells; Collagens; Cultured cells; Hepatocytes; Human organs; Liver; Perfusion; Rats; Scaffolds; Seeding; decellularization – ecm – ipsc – liver – regeneration – scaffold

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Frock, A. (2014). Utilizing Decellularized Porcine Liver Matrix as a Platform for 3-Dimensional Hepatic Cell Culture. (Masters Thesis). University of Florida. Retrieved from https://ufdc.ufl.edu/UFE0047605

Chicago Manual of Style (16^th Edition):

Frock, Adam. “Utilizing Decellularized Porcine Liver Matrix as a Platform for 3-Dimensional Hepatic Cell Culture.” 2014. Masters Thesis, University of Florida. Accessed January 18, 2021. https://ufdc.ufl.edu/UFE0047605.

MLA Handbook (7^th Edition):

Frock, Adam. “Utilizing Decellularized Porcine Liver Matrix as a Platform for 3-Dimensional Hepatic Cell Culture.” 2014. Web. 18 Jan 2021.

Vancouver:

Frock A. Utilizing Decellularized Porcine Liver Matrix as a Platform for 3-Dimensional Hepatic Cell Culture. [Internet] [Masters thesis]. University of Florida; 2014. [cited 2021 Jan 18]. Available from: https://ufdc.ufl.edu/UFE0047605.

Council of Science Editors:

Frock A. Utilizing Decellularized Porcine Liver Matrix as a Platform for 3-Dimensional Hepatic Cell Culture. [Masters Thesis]. University of Florida; 2014. Available from: https://ufdc.ufl.edu/UFE0047605

17. Garcha, Manveer Singh. Identifying key epigenetic regulators in human embryonic stem cell to definitive endoderm and the use of human endodermal progenitor cells for hepatocyte differentiation.

Degree: MA, Biological Sciences (Stem Cell, 2017, California State University – Sacramento

URL: http://hdl.handle.net/10211.3/193530

► Liver disease is a very serious problem that kills tens of thousands of people each year. In 2010, 50,000 people in the United States died… (more)

▼ Liver disease is a very serious problem that kills tens of thousands of people each year. In 2010, 50,000 people in the United States died due to some type of liver disease according to the Centers for Disease Control and Prevention. The American Cancer Society estimates that in 2013, more than 22,000 men and about 8,000 women in the United States will be diagnosed with primary liver cancer and intrahepatic bile duct cancer. Additionally, the incidence of primary hepatocellular carcinoma (liver cancer) is on the rise in the United States. A promising avenue of research for treating liver disease is the use of cellular therapy mediated approaches to support or replace damaged liver cells. It is possible to inject in vitro cultured human hepatocytes (hHCs) into liver injury sites in patients with diseased livers to take over or supplement the role of a patient's natural hHCs. Through our work, we are furthering our understanding of the differentiation of hHCs from human embryonic stem cells (ESCs) and endodermal progenitor cells (EPCs) so that hHCs can be cultured more effectively; bringing potentially lifesaving therapies closer to clinical application. Our specific aims were to optimize EPC culture protocols, characterize the hHC like phenotype of EPC derived hHCs, experiment with xenobiotic free or fully characterized EPC/EPH culture conditions, and identify upregulated demethylases in the ESC to hHC differentiation process. We cultured EPCs for up to 12 passages, optimized growth and differentiation protocols and tested their growth on different matrices, including vitronectin and human feeders . Our analysis ofEPC growth on human feeder cells, and EPH growth on feeder free and defined matrices/media conditions served as a pre-translational step towards the goal of bringing these cells to a clinical stage. We also assessed the effects of MEF concentration on EPC growth and phenotype, and found that using greater than previously recommended MEF concentrations did not have deleterious effects on EPC phenotype. We also did some preliminary work with xenobiotic free culture of EPCs that met with limited success. Human foreskin fibroblasts were used in lieu of Swiss-Webster MEFs. The human fibroblasts successfully formed a network, but the EPCs failed to grow and expand. Through qPCR we found meaningful increases over the differentiation period of genes encoding the secreted proteins albumin (ALB), and alpha-fetoprotein (AFP), functional proteins glucose transporter 2 (GLUT2), and metabolic/enzymatic proteins: histone acetyl transferase (HAT), fumarylacetoacetate hydrolase (FAH), alcohol dehydrogenase IA (ADRIA), cytochrome P450 4Al l (CYP4Al 1), and cytochrome P450 2D6 (CYP2D6). ELISA analysis confirmed the presence of albumin and its increased expression as EPHs matured. Our next step was to perform flow cytometry to confirm the presence of hepatic proteins. Through flow cytometry we saw an increase in positive expression of ALB, alpha-1-antitrypsin (AIAT), and AFP. The majority ofEPHs… Advisors/Committee Members: Peavy, Thomas R..

Subjects/Keywords: Hepatocytes; hHCs; Human embyronic stem cells; ESCs

…vitro cultured human hepatocytes (hHCs) are injected into liver injury sites in… …differentiation of hHCs from human embryonic stem cells (ESCs) and endodermal progenitor cells… …x28;Grapin-Botton, 2008). Human embryonic stem cells tend to spontaneously… …and human feeder growth conditions. 11 MATERIALS AND METHODS Human embryonic stem cells… …UCSF) or human fibroblasts with 3mL ofEPC culture media per well. The media consisted…

11 more images…

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Garcha, M. S. (2017). Identifying key epigenetic regulators in human embryonic stem cell to definitive endoderm and the use of human endodermal progenitor cells for hepatocyte differentiation. (Masters Thesis). California State University – Sacramento. Retrieved from http://hdl.handle.net/10211.3/193530

Chicago Manual of Style (16^th Edition):

Garcha, Manveer Singh. “Identifying key epigenetic regulators in human embryonic stem cell to definitive endoderm and the use of human endodermal progenitor cells for hepatocyte differentiation.” 2017. Masters Thesis, California State University – Sacramento. Accessed January 18, 2021. http://hdl.handle.net/10211.3/193530.

MLA Handbook (7^th Edition):

Garcha, Manveer Singh. “Identifying key epigenetic regulators in human embryonic stem cell to definitive endoderm and the use of human endodermal progenitor cells for hepatocyte differentiation.” 2017. Web. 18 Jan 2021.

Vancouver:

Garcha MS. Identifying key epigenetic regulators in human embryonic stem cell to definitive endoderm and the use of human endodermal progenitor cells for hepatocyte differentiation. [Internet] [Masters thesis]. California State University – Sacramento; 2017. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/10211.3/193530.

Council of Science Editors:

Garcha MS. Identifying key epigenetic regulators in human embryonic stem cell to definitive endoderm and the use of human endodermal progenitor cells for hepatocyte differentiation. [Masters Thesis]. California State University – Sacramento; 2017. Available from: http://hdl.handle.net/10211.3/193530

University of Helsinki

18. Peltoniemi, Pasi. Human Embryonic and Induced Pluripotent Stem Cell-Derived Cells as Preclinical Tools in Drug Discovery and Development.

Degree: Farmaceutiska fakulteten, 2012, University of Helsinki

URL: http://hdl.handle.net/10138/32824

► Ihmisalkion kantasolujen (hESC-solut) ja indusoitujen pluripotenttien kantasolujen (hiPSCsolut) erityispiirteitä ovat lähes rajaton jakautumiskyky ja kyky erilaistua moniksi solutyypeiksi. Molemmilla solutyypeillä on hyvät ja huonot puolensa,… (more)

▼ Ihmisalkion kantasolujen (hESC-solut) ja indusoitujen pluripotenttien kantasolujen (hiPSCsolut) erityispiirteitä ovat lähes rajaton jakautumiskyky ja kyky erilaistua moniksi solutyypeiksi. Molemmilla solutyypeillä on hyvät ja huonot puolensa, mutta nykyinen käsitys on, että hESC- ja hiPSC-solut ennemminkin täydentävät kuin korvaavat toisiaan. Kantasolututkimus kehittyy nopeasti ja kohtaa koko ajan uusia tieteellisiä ongelmia sekä eettisiä haasteita. hESC- ja hiPSC-soluteknologiat ovat tuoneet paljon mahdollisuuksia lääkekehitykseen. Ne voivat tulevaisuudessa korvata nykyisin käytössä olevia prekliinisiä toksisuus- ja tehoseulontamenetelmiä ja auttaa havaitsemaan uusien lääkeainekandidaattimolekyylien ei-toivotut vaikutukset jo lääkekehitysprosessin aikaisessa vaiheessa. Haastava erilaistamisprosessi on yksi käyttöönoton isoimmista esteistä. Tutkimusryhmämme aikaisempi tutkimus osoitti, että liver cell-solujen soluväliaine edistää hESC-solujen erilaistamista maksasolujen kaltaisiksi soluiksi. Tämän tutkimuksen tarkoitus oli luoda kemiallisesti selkeästi määriteltävät soluväliainematriksit, jotka tukevat hESC-solujen erilaistumista maksasolujen kaltaisiksi soluiksi. Tutkimuksen tulokset osoittavat, että solujen soluväliaine sisältää fibronektiini-, laminiinis-proteiineja. Karakterisoinnin jälkeen tavoite oli tutkia, millä näistä soluväliaineproteiineista on vaikutusta erilaistamisprosessiin. Kolmivaiheisessa erilaistamisprosessissa käytettiin erilaisia soluväliaineproteiinimatrikseja. hESC-solut erilaistettiin ensin definitiivisen endodermin soluiksi, jotka erilaistettiin edelleen HNF4α- and AFP-proteiineja ilmentäviksi maksan esisoluiksi. Lopuksi maksan esisolut erilaistettiin maksasolujen kaltaisiksi soluiksi. Erilaistetut solut ilmentivät lähetti-RNA-tasolla albumiinia, sytokeratiini 8:a ja 18:a, α-antitrypsiiniä ja BCRP-proteiiniä. Solut muistuttivat ulkonäöltään hepatosyyttejä, muodostivat sytoplasmisia rakkuloita ja erittivät albumiinia. Soluväliainematriksit tukivat hESC-solujen erilaistumista maksasolujen kaltaisiksi soluiksi. Tutkimuksessa luotiin tehokas ja kemiallisesti määritelty systeemi, jonka avulla voidaan tuottaa maksansolun kaltaisia soluja. Sitä voidaan hyödyntää lääketutkimuksessa ja kehitysbiologisessa perustutkimuksessa.

Subjects/Keywords: human embryonic stem cells; human induced pluripotent stem cells; drug discovery and development; differentiation; hepatocytes; extracellular matrix; ihmisalkion kantasolut; ihmisen indusoidut pluripotentit kantasolut; lääkekehitys; erilaistaminen; maksasolut; soluväliaine; Biofarmaci; Biopharmacy; Biofarmasia

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Peltoniemi, P. (2012). Human Embryonic and Induced Pluripotent Stem Cell-Derived Cells as Preclinical Tools in Drug Discovery and Development. (Masters Thesis). University of Helsinki. Retrieved from http://hdl.handle.net/10138/32824

Chicago Manual of Style (16^th Edition):

Peltoniemi, Pasi. “Human Embryonic and Induced Pluripotent Stem Cell-Derived Cells as Preclinical Tools in Drug Discovery and Development.” 2012. Masters Thesis, University of Helsinki. Accessed January 18, 2021. http://hdl.handle.net/10138/32824.

MLA Handbook (7^th Edition):

Peltoniemi, Pasi. “Human Embryonic and Induced Pluripotent Stem Cell-Derived Cells as Preclinical Tools in Drug Discovery and Development.” 2012. Web. 18 Jan 2021.

Vancouver:

Peltoniemi P. Human Embryonic and Induced Pluripotent Stem Cell-Derived Cells as Preclinical Tools in Drug Discovery and Development. [Internet] [Masters thesis]. University of Helsinki; 2012. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/10138/32824.

Council of Science Editors:

Peltoniemi P. Human Embryonic and Induced Pluripotent Stem Cell-Derived Cells as Preclinical Tools in Drug Discovery and Development. [Masters Thesis]. University of Helsinki; 2012. Available from: http://hdl.handle.net/10138/32824

19. Bellamri, Medjda. Activation métabolique et génotoxicité des Amines Hétérocycliques Aromatiques (AHA) chez l’Homme : Metabolic activation and genotoxicity of Heterocyclic Amines Aromatics (AHA) in humans.

Degree: Docteur es, Biologie, 2016, Rennes 1

URL: http://www.theses.fr/2016REN1B033

►

Les amines hétérocycliques aromatiques (AHA) sont des contaminants de l'environnement et de l'alimentation, majoritairement formés lors de la cuisson de viande et poisson ainsi que… (more)

▼

Les amines hétérocycliques aromatiques (AHA) sont des contaminants de l'environnement et de l'alimentation, majoritairement formés lors de la cuisson de viande et poisson ainsi que dans la fumée de cigarette et les gaz d'échappements. Les AHA sont mutagènes chez la bactérie, cancérogènes multi-sites chez le rongeur et sont classées comme cancérogènes possibles ou probables chez l'Homme par l'IARC. Il est aujourd'hui indispensable de caractériser des biomarqueurs d'exposition dérivés des AHA (adduits à l'ADN et métabolites) pour améliorer l'estimation du risque chez l'Homme. Des résultats de l'équipe ont démontré que le 2-amino-9H-pyrido[2,3-b]indole (AαC) forme des niveaux d'adduits à l'ADN élevés dans les hépatocytes humains. Ces niveaux sont plus élevés que ceux formés par les autres AHA. L'objectif de cette thèse est de mieux comprendre le potentiel génotoxique d'AαC chez l'Homme. Nos travaux ont démontré que les adduits à l'ADN dérivés d'AαC sont persistants dans les hépatocytes humains et formés à des doses aussi faibles que 1nM. De plus, le CYP1A2 a été confirmé comme enzyme majoritaire dans la bioactivation d'AαC dans le foie humain. Nous avons également caractérisé les métabolites majeurs dérivés d'AαC dans les hépatocytes humains. Cette étude a permis d'établir pour la première fois une corrélation entre l'activité catalytique du CYP1A2, la formation d'AαC-HN2-O-Gl et la formation des adduits à l'ADN dérivés d'AαC. Le métabolite AαC-HN2-O-Gl étant réactif vis-à-vis de l'ADN in vitro, nos travaux confortent l'hypothèse que la voie des UDP-Glucuronosyltransférases (UGTs) est une nouvelle voie de bioactivation d'AαC dans le foie humain. De plus, nous avons montré que les adduits à l'ADN dérivés des AHA sont formés dans les lymphocytes T humains activés et en particulier les adduits en position C8 de la guanine dérivés d'AαC. Au total, ces travaux ont permis l'identification de métabolites stables et des adduits à l'ADN, potentiels biomarqueurs d'exposition à AαC, qui sont indispensables pour une meilleure estimation du risque génotoxique d'AαC chez l'Homme.

Heterocyclic aromatic amines (HAA) are environmental and food contaminants, mainly formed during meat and fish cooking, but also in cigarette smoke and exhaust gaz. HAA are mutagenic in bacteria, carcinogenic in rodents and are classified as possible or probable human carcinogens by IARC. Today it is essential to characterize exposure biomarkers i.e. DNA adducts and metabolites, to assess the human risk associated with HAA. The research team has previously demonstrated that 2-amino-9H-pyrido[2,3-b]indole (AαC) form high levels of DNA adducts in human hepatocytes. These levels are greater that those derived from other HAAs. Thus, the aim of this thesis was to better understand the genotoxic potential of AαC in human. We demonstrated that in human hepatocytes, DNA adducts derived from AαC are persistent and formed at doses as low as 1nM. Moreover, we confirmed that CYP1A2 is the major enzyme implicated in the bioactivation of AαC in human liver. We have…

Advisors/Committee Members: Langouet-Prigent, Sophie (thesis director), Le Hegarat, Ludovic (thesis director).

Subjects/Keywords: Amines hétérocycliques aromatiques; Hépatocytes humains primaires; Activation métabolique; Cyp1a2; Adduits à l'ADN; Génotoxicité; Cancer; Heterocyclic Aromatic Amines; Primary Human Hepatocytes; Metabolic Activation; Cyp1a2; DNA Adducts; Genotoxicity; Cancer

Record Details Similar Records Cite « Share

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Bellamri, M. (2016). Activation métabolique et génotoxicité des Amines Hétérocycliques Aromatiques (AHA) chez l’Homme : Metabolic activation and genotoxicity of Heterocyclic Amines Aromatics (AHA) in humans. (Doctoral Dissertation). Rennes 1. Retrieved from http://www.theses.fr/2016REN1B033

Chicago Manual of Style (16^th Edition):

Bellamri, Medjda. “Activation métabolique et génotoxicité des Amines Hétérocycliques Aromatiques (AHA) chez l’Homme : Metabolic activation and genotoxicity of Heterocyclic Amines Aromatics (AHA) in humans.” 2016. Doctoral Dissertation, Rennes 1. Accessed January 18, 2021. http://www.theses.fr/2016REN1B033.

MLA Handbook (7^th Edition):

Bellamri, Medjda. “Activation métabolique et génotoxicité des Amines Hétérocycliques Aromatiques (AHA) chez l’Homme : Metabolic activation and genotoxicity of Heterocyclic Amines Aromatics (AHA) in humans.” 2016. Web. 18 Jan 2021.

Vancouver:

Bellamri M. Activation métabolique et génotoxicité des Amines Hétérocycliques Aromatiques (AHA) chez l’Homme : Metabolic activation and genotoxicity of Heterocyclic Amines Aromatics (AHA) in humans. [Internet] [Doctoral dissertation]. Rennes 1; 2016. [cited 2021 Jan 18]. Available from: http://www.theses.fr/2016REN1B033.

Council of Science Editors:

Bellamri M. Activation métabolique et génotoxicité des Amines Hétérocycliques Aromatiques (AHA) chez l’Homme : Metabolic activation and genotoxicity of Heterocyclic Amines Aromatics (AHA) in humans. [Doctoral Dissertation]. Rennes 1; 2016. Available from: http://www.theses.fr/2016REN1B033

20. Bricks, Thibault. Développement d’un dispositif microfluidique ayant pour objectif l’étude des effets de premiers passages intestinaux et hépatiques : Development of a new microfluidic platform in order to study intestinal and hepatic first pass effects.

Degree: Docteur es, Bio-Ingénierie, Biomécanique, Biomatériaux, 2014, Compiègne

URL: http://www.theses.fr/2014COMP2151

►

Le développement de méthodes in vitro fiables et prédictives représente à l’heure actuelle un véritable défi. En effet, la demande en méthodes alternatives à l’expérimentation… (more)

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Le développement de méthodes in vitro fiables et prédictives représente à l’heure actuelle un véritable défi. En effet, la demande en méthodes alternatives à l’expérimentation animale n’a cessé de croître ces dernières années du fait de la mise en place de législations limitant par considérations éthiques l’utilisation de ces modèles in vivo. De plus, ce besoin a été renforcé par le règlement européen REACH (Registration, Evaluation, Authorization and Restriction of Chemicals) imposant aux industriels de valider l’innocuité de nombreuses substances déjà commercialisées. Toutefois, les modèles in vitro classiques consistant en la culture simple de cellules en monocouche dans des boîtes de Petri ne permettent pas de conserver les propriétés initiales de ces cellules et de retranscrire les conditions et l’environnement cellulaire des organes in vivo. Le développement de méthodes alternatives in vitro prédictives s’avèrent donc crucial en particulier pour mimer le fonctionnement de deux organes : l’intestin et le foie. En effet, ces deux organes sont largement impliqués dans les processus d’Absorption, Distribution, Métabolisme et Excrétion (ADME) de la plupart des xénobiotiques ingérés. C’est pour ces raisons que nous avons testé la faisabilité de l’une de ces méthodes in vitro alternative permettant d’associer une barrière intestinale à la culture dynamique de cellules hépatiques au sein de microsystèmes dans le cadre de ce doctorat. Cette coculture est effectuée au sein du dispositif appelé IIDMP (Integrated Insert in a Dynamic Microfluidic Platform). Nous avons décidé de tester d’une part l’influence de la culture dynamique et d’autre part d’éventuelles interactions entre les cellules intestinales et hépatiques sur la fonctionnalité et l’activité métabolique de ces deux types cellulaires. Les résultats obtenus durant ce doctorat ont permis d’atteindre 4 objectifs :- Développer un dispositif fiable en termes de fonctionnalité (fluidique, robustesse…).- Mettre en évidence l’innocuité du dispositif lorsque des cellules de lignée et primaires y étaient cultivées.- Démontrer les avantages de l’utilisation de ce dispositif comparativement à l’utilisation de modèles classiques in vitro, en particulier avec des cellules de lignée.- Démontrer que l’utilisation de ce dispositif permettait de mettre en évidence des phénomènes d’interactions entre cellules intestinales et hépatiques notamment sur l’activité du CYP1A2 des hépatocytes qu’ils soient issus d’une lignée ou de cultures primaires.

The development of reliable and predictive in vitro methods is a real challenge. Indeed, the demand for alternative methods to animal experimentation has been growing in recent years due to the introduction of legislation limiting the use of these models in vivo by ethical considerations. Moreover, this need was amplified by regulations such as the European REACH (Registration, Evaluation, Authorization and Restriction of Chemicals) requiring the safety validation of many substances. However, the conventional in vitro model consisting in a…

Advisors/Committee Members: Leclerc, Éric (thesis director).

Subjects/Keywords: Coculture; Hépatocytes primaires humains; Effets de premiers passages; Microsystèmes; IIDMP; IDCCM; Caco-2 TC7; HepG2 C3A; Intestine; Liver; First pass metabolism; Microfluidic; Microsystems; Human primary hepatocytes; Phenacetin; Clearances

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Bricks, T. (2014). Développement d’un dispositif microfluidique ayant pour objectif l’étude des effets de premiers passages intestinaux et hépatiques : Development of a new microfluidic platform in order to study intestinal and hepatic first pass effects. (Doctoral Dissertation). Compiègne. Retrieved from http://www.theses.fr/2014COMP2151

Chicago Manual of Style (16^th Edition):

Bricks, Thibault. “Développement d’un dispositif microfluidique ayant pour objectif l’étude des effets de premiers passages intestinaux et hépatiques : Development of a new microfluidic platform in order to study intestinal and hepatic first pass effects.” 2014. Doctoral Dissertation, Compiègne. Accessed January 18, 2021. http://www.theses.fr/2014COMP2151.

MLA Handbook (7^th Edition):

Bricks, Thibault. “Développement d’un dispositif microfluidique ayant pour objectif l’étude des effets de premiers passages intestinaux et hépatiques : Development of a new microfluidic platform in order to study intestinal and hepatic first pass effects.” 2014. Web. 18 Jan 2021.

Vancouver:

Bricks T. Développement d’un dispositif microfluidique ayant pour objectif l’étude des effets de premiers passages intestinaux et hépatiques : Development of a new microfluidic platform in order to study intestinal and hepatic first pass effects. [Internet] [Doctoral dissertation]. Compiègne; 2014. [cited 2021 Jan 18]. Available from: http://www.theses.fr/2014COMP2151.

Council of Science Editors:

Bricks T. Développement d’un dispositif microfluidique ayant pour objectif l’étude des effets de premiers passages intestinaux et hépatiques : Development of a new microfluidic platform in order to study intestinal and hepatic first pass effects. [Doctoral Dissertation]. Compiègne; 2014. Available from: http://www.theses.fr/2014COMP2151

21. Ilboudo, Adeodat. Phosphatidylinositol 4 -Kinases de type III hépatiques : implication au cours de l'infection par le virus de l'hépatite C et lien avec le carcinome hépatocellulaire : Type III Phosphatidylinositol 4-kinases in the liver : involvement during Hepatitis C Virus infection and link with hepatocellular carcinoma.

Degree: Docteur es, Biologie et sciences de la santé, 2013, Rennes 1

URL: http://www.theses.fr/2013REN1B006

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Le virus de l’hépatite C (VHC) est l’un des principaux facteurs étiologiques du carcinome hépatocellulaire. Le traitement des hépatites virales C a été récemment amélioré… (more)

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Le virus de l’hépatite C (VHC) est l’un des principaux facteurs étiologiques du carcinome hépatocellulaire. Le traitement des hépatites virales C a été récemment amélioré grâce à une trithérapie (interféron, ribavirine et anti-protéase virale). Néanmoins l’importance des effets secondaires et l’émergence de mutants résistants nécessitent de découvrir de nouveaux antiviraux. Dans ce contexte, notre équipe a récemment découvert que les phosphatidylinositol 4-kinases de type III (PI4KIIIα et PI4KIIIβ) étaient indispensables à la propagation du virus dans une lignée hépatique humaine, et ce, à 2 étapes de son cycle biologique : l’entrée et la réplication. L’objectif du présent travail était de poursuivre la validation de ces nouvelles cibles thérapeutiques potentielles, en approfondissant nos connaissances sur la dépendance du virus à l’égard de ces kinases au cours de son entrée. Pour cela, nous avons utilisé le modèle des hépatocytes humains primaires, système in vitro plus proche du contexte physiologique que les modèles utilisés jusqu’à présent et qui étaient basés sur l’exploitation de lignées. Deux axes ont été développés : Vérification de l’importance de l’activité kinase des PI4KIIIs au cours de l’entrée du VHC dans les hépatocytes humains primaires, à travers une approche chimique ; Validation de l’implication de ces kinases et de leur activité enzymatique au cours de l’entrée virale grâce à une approche génétique basée sur l’ARN interférence et la restauration de phénotype. En parallèle, nous avons étudié l’expression de PI4KIIIα au cours de pathologies hépatiques. Nos résultats suggèrent une implication de PI4KIIIα au cours de l’entrée du VHC dans les hépatocytes humains primaires, mais restent à confirmer quant à l’implication de PI4KIIIβ. Par ailleurs, l’analyse de l’expression de PI4KIIIα dans le carcinome hépatocellulaire (CHC) conduit à proposer cette kinase comme un nouveau marqueur moléculaire, qui pourrait améliorer les modèles de pronostic déjà établis et pourrait conduire au développement de nouvelles approches thérapeutiques pour les patients atteints d’un CHC, quelque soit l’étiologie.

Hepatitis C virus (HCV) is one of the leading causes of hepatocellular carcinoma. Therapeutic treatment against the virus has been recently improved by a tritherapy including pegylated interferon, ribavirin and antiviral protease. Nevertheless, the importance of side effects and the emergence of resistant mutants require the development of new antivirals. In this context, our team has recently discovered that Type III phosphatidylinositol 4-kinases (PI4KIIIα and PI4KIIIβ) are essential for the propagation of the virus in a human hepatic cell line at the entry and replication steps. To further characterize these potential therapeutic targets, we investigate the implication of these kinases during the HCV entry, using primary human hepatocytes, a model closer to the in vivo conditions. Two lines of research were developed: Verification of the importance of the kinase activity of PI4KIIIs during HCV entry in primary…

Advisors/Committee Members: Michelet, Christian (thesis director), Le seyec, Jacques (thesis director).

Subjects/Keywords: Virus de l'hépatite c; Carcinome hépatocellulaire; Hépatocytes humains primaires; Infection; Phosphatidylinositol 4-kinases; Hepatitis C virus; Hepatocellular carcinoma; Primary human hepatocytes; Infection; Phosphatidylinositol 4-kinases

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ilboudo, A. (2013). Phosphatidylinositol 4 -Kinases de type III hépatiques : implication au cours de l'infection par le virus de l'hépatite C et lien avec le carcinome hépatocellulaire : Type III Phosphatidylinositol 4-kinases in the liver : involvement during Hepatitis C Virus infection and link with hepatocellular carcinoma. (Doctoral Dissertation). Rennes 1. Retrieved from http://www.theses.fr/2013REN1B006

Chicago Manual of Style (16^th Edition):

Ilboudo, Adeodat. “Phosphatidylinositol 4 -Kinases de type III hépatiques : implication au cours de l'infection par le virus de l'hépatite C et lien avec le carcinome hépatocellulaire : Type III Phosphatidylinositol 4-kinases in the liver : involvement during Hepatitis C Virus infection and link with hepatocellular carcinoma.” 2013. Doctoral Dissertation, Rennes 1. Accessed January 18, 2021. http://www.theses.fr/2013REN1B006.

MLA Handbook (7^th Edition):

Ilboudo, Adeodat. “Phosphatidylinositol 4 -Kinases de type III hépatiques : implication au cours de l'infection par le virus de l'hépatite C et lien avec le carcinome hépatocellulaire : Type III Phosphatidylinositol 4-kinases in the liver : involvement during Hepatitis C Virus infection and link with hepatocellular carcinoma.” 2013. Web. 18 Jan 2021.

Vancouver:

Ilboudo A. Phosphatidylinositol 4 -Kinases de type III hépatiques : implication au cours de l'infection par le virus de l'hépatite C et lien avec le carcinome hépatocellulaire : Type III Phosphatidylinositol 4-kinases in the liver : involvement during Hepatitis C Virus infection and link with hepatocellular carcinoma. [Internet] [Doctoral dissertation]. Rennes 1; 2013. [cited 2021 Jan 18]. Available from: http://www.theses.fr/2013REN1B006.

Council of Science Editors:

Ilboudo A. Phosphatidylinositol 4 -Kinases de type III hépatiques : implication au cours de l'infection par le virus de l'hépatite C et lien avec le carcinome hépatocellulaire : Type III Phosphatidylinositol 4-kinases in the liver : involvement during Hepatitis C Virus infection and link with hepatocellular carcinoma. [Doctoral Dissertation]. Rennes 1; 2013. Available from: http://www.theses.fr/2013REN1B006

KTH

22. Truvé, Malin. New applications of Antrad Medical's thawing technology : Applications within the clinical and laboratory segment.

Degree: Technology and Health (STH), 2016, KTH

URL: http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-190778

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Antrad Medical has developed an ultra-fast blood plasma thawing device named UFT100. The method is based on thawing with an oscillating electrical field and… (more)

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Antrad Medical has developed an ultra-fast blood plasma thawing device named UFT100. The method is based on thawing with an oscillating electrical field and unlike water baths it is a dry method. Fast and homogeneous thawing is achieved. This project investigates new possible applications where this thawing technology could be used within the clinical and laboratory segment. The aim was to identify existing thawing and heating methods for a substance that can be improved and potentially replaced with the UFT100. Data has been collected through literature research and interviews with Antrad Medical and specialists working in Sweden. The specialists are working within the clinical and laboratory field. A number of criteria for establishment of the UFT100 were set up and used as a tool for evaluation. The substances investigated during this project were infusion medicine, embryos, substance in a sampling tube, protein based pharmaceuticals, stem cells for transplantation and research, biobank sampling tubes, cryoprecipitate, human hepatocytes, live vaccines, API, BDS, intermediate and antibodies. Two applications within the clinical area are found probable, stem cells and cryoprecipitate. Further investigation for human hepatocytes, API, BDS, intermediate and pharmaceuticals is needed.

Antrad Medical har utvecklat en ultra-snabb blodplasmaupptinare kallad UFT100. Det är till skillnad från vattenbad en torr metod baserad på upptining med hjälp av oscillerande elektriska fält. Genom detta uppnås snabb och homogen upptining. Detta projekt undersöker nya möjliga kliniska- och laboratorietillämpningar för upptiningstekniken. Målet var att identifiera substanser vars nuvarande upptining- och uppvärmningsteknik kan förbättras och kanske ersättas med UFT100. Data har samlats in genom litteratursökning och genom intervjuer med Antrad Medical och specialister som arbetar i Sverige. Specialisterna arbetar inom kliniska områden och laboratorieverksamheter. Ett antal kriterier för etablering av UFT100 sattes upp och användes för utvärdering. Substanserna som undersöktes under projektets gång var infusionsmedicin, embryon, innehåll i ett provrör, proteinbaserade läkemedel, stamceller för transplantation och forskning, biobank-provrör, kryoprecipitat, humana hepatocyter, levande vaccin, aktiva substanser, läkemedelssubstanser, intermediat och antikroppar. Två tillämpningar inom det kliniska området ses som möjliga, stamceller och kryoprecipitat. Humana hepatocyter, aktiva substanser, läkemedelssubstanser och intermediat behöver undersökas vidare.

Subjects/Keywords: Antrad Medical; thawing; thawing methods; thawing device; heating; stem cells; cryoprecipitate; human hepatocytes; API; BDS; intermediate; pharmaceuticals; Antrad Medical; upptining; upptiningstekniker; upptiningsapparat; uppvärmning; stamceller; kryoprecipitat; humana hepatocyter; läkemedel

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Truvé, M. (2016). New applications of Antrad Medical's thawing technology : Applications within the clinical and laboratory segment. (Thesis). KTH. Retrieved from http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-190778

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Truvé, Malin. “New applications of Antrad Medical's thawing technology : Applications within the clinical and laboratory segment.” 2016. Thesis, KTH. Accessed January 18, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-190778.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Truvé, Malin. “New applications of Antrad Medical's thawing technology : Applications within the clinical and laboratory segment.” 2016. Web. 18 Jan 2021.

Vancouver:

Truvé M. New applications of Antrad Medical's thawing technology : Applications within the clinical and laboratory segment. [Internet] [Thesis]. KTH; 2016. [cited 2021 Jan 18]. Available from: http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-190778.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Truvé M. New applications of Antrad Medical's thawing technology : Applications within the clinical and laboratory segment. [Thesis]. KTH; 2016. Available from: http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-190778

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

23. Hackett, Tia. Keys for maturation of human embryonic stem cell derived hepatocytes may lie in over expression of hepatic maturation genes and epigenetics.

Degree: MA, Biological Sciences (Stem Cell, 2017, California State University – Sacramento

URL: http://hdl.handle.net/10211.3/193529

► The liver is the largest solid organ that performs many vital functions systemically for the body and contains about 13% of the blood at any… (more)

▼ The liver is the largest solid organ that performs many vital functions systemically for the body and contains about 13% of the blood at any given time. The vital functions of the liver are attributive to the combined and cooperative functions of the different cell types found within liver tissue. There are two main categories of cell types within the liver; parenchymal and nonparenchymal. Parenchymal cells, also known as hepatocytes, are the primary source of most of the liver's functions, but rely on neighboring and supportive nonparenchymal cells for regulation of their functions. Unfortunately, since hepatocytes are involved in so many vital functions, the systemic functions of the liver can be dramatically affected when hepatocytes become damaged or undergo apoptosis. For this reason, biological researchers have been looking for ways to replace hepatocyte populations as a means to restore the liver's functions. Many researchers, in turn, believe that human embryonic stem cells (hESC) may be the solution. Even though hESCs have shown promise for differentiating into hepatocytes, producing a mature enough population in vitro has been proven more difficult. While the exact molecular mechanisms of producing a fully mature population ofhepatocytes remain largely unknown, exogenous over expression of mature hepatic genes known as, liver emiched transcription factors (LETFs) through a viral vector delivery system may allow for a more mature and functional phenotype. Another insight into producing more mature hepatocytes may lie in studying epigenetic changes, such as changes in histone methylation patterns. The Jumonji C-domain-containing histone demethylase family is composed of 30 enzymes that are involved in changing histone methylation patterns and may have roles in the epigenetic changes and modifications found in mature hepatocytes. The current hepatocyte differentiation protocol successfully differentiated H9 hESC stem cell line to immature hepatocytes. Preliminary analysis of exogenous LETF gene expression has shown that certain over expressed genes delivered through adenoviral vectors such as, CCAAT/enhancer-binding protein beta (C/EBPB) and hepatocyte nuclear factor I homeobox A (HNFIA), have been shown to increase expression of genes responsible for contributing to mature hepatocyte functions. The investigation into the epigenetics ofhepatocyte derived hESCs has shown that certain Jumonji C-domaincontaining histone demethylase family members, such as MINA53, JHDM3 and HR, have a higher expression in conjunction with a higher secretion of albumin and lower secretion of alpha-fetoprotein. While all these findings are still relatively inconclusive, they provide a major insight for future research studies and goals. Future studies for over expression of genes through adenoviral vector delivery will include replication of initial analysis and functional metabolic activity tests. Future studies for Jumonji C-domain-containing histone demethylase family members will include… Advisors/Committee Members: Peavy, Thomas R..

Subjects/Keywords: Parenchymal cells; Hepatocytes; Human embyronic stem cells; hESC

…15 Culture and Maintenance of Primary Hepatocytes… …15 Culture and Maintenance of human Embryonic Stem Cells (hESCs) ........... 16… …17 Differentiation of DE towards Hepatocytes and Hepatocyte Maintenance ... 18… …ofhESC-Derived Hepatocytes ........................................ 23 X Whole Protein… …Four Growth Factor Cocktail Induces Immature Hepatocytes from DE. 30 Expression of Specific…

11 more images…

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Hackett, T. (2017). Keys for maturation of human embryonic stem cell derived hepatocytes may lie in over expression of hepatic maturation genes and epigenetics. (Masters Thesis). California State University – Sacramento. Retrieved from http://hdl.handle.net/10211.3/193529

Chicago Manual of Style (16^th Edition):

Hackett, Tia. “Keys for maturation of human embryonic stem cell derived hepatocytes may lie in over expression of hepatic maturation genes and epigenetics.” 2017. Masters Thesis, California State University – Sacramento. Accessed January 18, 2021. http://hdl.handle.net/10211.3/193529.

MLA Handbook (7^th Edition):

Hackett, Tia. “Keys for maturation of human embryonic stem cell derived hepatocytes may lie in over expression of hepatic maturation genes and epigenetics.” 2017. Web. 18 Jan 2021.

Vancouver:

Hackett T. Keys for maturation of human embryonic stem cell derived hepatocytes may lie in over expression of hepatic maturation genes and epigenetics. [Internet] [Masters thesis]. California State University – Sacramento; 2017. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/10211.3/193529.

Council of Science Editors:

Hackett T. Keys for maturation of human embryonic stem cell derived hepatocytes may lie in over expression of hepatic maturation genes and epigenetics. [Masters Thesis]. California State University – Sacramento; 2017. Available from: http://hdl.handle.net/10211.3/193529

24. Rose, Sophie. Optimisation de la prolifération et de la différenciation des hépatocytes humains dans un nouveau modèle de culture 3D : application à l'étude des Amines Hétérocycliques Aromatiques (AHAs) : Optimization of the proliferation and differentiation of human hepatocytes in a new 3D culture model : application to the study of Heterocyclic Aromatic Amines (HAAs).

Degree: Docteur es, Toxicologie, 2018, Rennes 1

URL: http://www.theses.fr/2018REN1B022

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Le foie joue un rôle prépondérant dans la biotransformation et l’élimination des xénobiotiques. Le développement de modèles cellulaires hépatiques humains pertinents représente un enjeu majeur… (more)

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Le foie joue un rôle prépondérant dans la biotransformation et l’élimination des xénobiotiques. Le développement de modèles cellulaires hépatiques humains pertinents représente un enjeu majeur afin d’étudier in vitro chez l’Homme la bioactivation de contaminants préoccupants, les altérations à l’ADN qui en dérivent et leur pouvoir mutagène/cancérigène. Ces analyses constituent des étapes clés pour l’identification de biomarqueurs d’exposition indispensables à l’évaluation du risque au niveau des individus et dans les populations. Lors de cette thèse, nous avons mis au point un modèle original de culture 3D en gels de collagène dans lequel les hépatocytes humains s’organisent en sphéroïdes polarisés. Par cette approche, nous avons démontré, pour la première fois, la capacité des hépatocytes primaires cultivés en 3D à proliférer in vitro. De plus, une réinitialisation du cycle cellulaire peut être obtenue après l’inhibition transitoire de la voie de signalisation des MAPKs MEK1/2-ERK1/2. Dans nos conditions, les hépatocytes primaires et transformés expriment des fonctions hépatiques hautement différenciées pendant plusieurs semaines de culture, et les cellules HepaRG se différencient après seulement quelques jours de culture, sans ajout de DMSO. Dans ce contexte, nous avons étudié la génotoxicité d’une classe de contaminants de l’environnement et de l’alimentation, les Amines Hétérocycliques Aromatiques (AHAs). Nos résultats démontrent la pertinence de la culture cellulaire en gels de collagène pour l’identification et la quantification des adduits à l’ADN et les études de toxicité aiguë et chronique dans les hépatocytes humains. Ces travaux représentent une avancée majeure car ils lèvent un verrou au développement de nombreuses applications biotechnologiques. L’établissement de tels modèles d’hépatocytes humains proliférants in vitro permet d’évaluer le pouvoir mutagène des contaminants de l’environnement.

The liver plays a major role in metabolism and elimination of xenobiotics. The development of relevant human in vitro models represents a major challenge to study the hepatic bioactivation of drugs and contaminants, the DNA alterations and their mutagenic/carcinogenic potential. These analyzes are key steps for identifying biomarkers of exposure that are essential for assessing risk in populations. In this study, we developed an original cellular model of 3D culture in collagen gels in which human hepatocytes are well organized in spheroids with an apico-basal polarity. By this approach, we demonstrated, for the first time, the ability of these 3D primary human hepatocytes to proliferate in vitro. Furthermore, a new cell cycle can be reinitiate after transient MAPKs MEK1/2-ERK1/2 signaling pathway inhibition. Under our conditions, primary and transformed hepatocytes express highly differentiated hepatic functions for several weeks of culture, and HepaRG cells differentiate after only few days of culture without addition of DMSO. In this context, we investigated the genotoxicity of a class of environmental and…

Advisors/Committee Members: Langouet-Prigent, Sophie (thesis director).

Subjects/Keywords: Hépatocytes humains primaires et transformés; Modèle de culture 3D; Prolifération; Différenciation; Adduits à l’ADN; Génotoxicité; Human primary and transformed hepatocytes; 3d; Proliferation; Long-Term differenciation; DNA adducts; Genotoxicity

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Rose, S. (2018). Optimisation de la prolifération et de la différenciation des hépatocytes humains dans un nouveau modèle de culture 3D : application à l'étude des Amines Hétérocycliques Aromatiques (AHAs) : Optimization of the proliferation and differentiation of human hepatocytes in a new 3D culture model : application to the study of Heterocyclic Aromatic Amines (HAAs). (Doctoral Dissertation). Rennes 1. Retrieved from http://www.theses.fr/2018REN1B022

Chicago Manual of Style (16^th Edition):

Rose, Sophie. “Optimisation de la prolifération et de la différenciation des hépatocytes humains dans un nouveau modèle de culture 3D : application à l'étude des Amines Hétérocycliques Aromatiques (AHAs) : Optimization of the proliferation and differentiation of human hepatocytes in a new 3D culture model : application to the study of Heterocyclic Aromatic Amines (HAAs).” 2018. Doctoral Dissertation, Rennes 1. Accessed January 18, 2021. http://www.theses.fr/2018REN1B022.

MLA Handbook (7^th Edition):

Rose, Sophie. “Optimisation de la prolifération et de la différenciation des hépatocytes humains dans un nouveau modèle de culture 3D : application à l'étude des Amines Hétérocycliques Aromatiques (AHAs) : Optimization of the proliferation and differentiation of human hepatocytes in a new 3D culture model : application to the study of Heterocyclic Aromatic Amines (HAAs).” 2018. Web. 18 Jan 2021.

Vancouver:

Rose S. Optimisation de la prolifération et de la différenciation des hépatocytes humains dans un nouveau modèle de culture 3D : application à l'étude des Amines Hétérocycliques Aromatiques (AHAs) : Optimization of the proliferation and differentiation of human hepatocytes in a new 3D culture model : application to the study of Heterocyclic Aromatic Amines (HAAs). [Internet] [Doctoral dissertation]. Rennes 1; 2018. [cited 2021 Jan 18]. Available from: http://www.theses.fr/2018REN1B022.

Council of Science Editors:

Rose S. Optimisation de la prolifération et de la différenciation des hépatocytes humains dans un nouveau modèle de culture 3D : application à l'étude des Amines Hétérocycliques Aromatiques (AHAs) : Optimization of the proliferation and differentiation of human hepatocytes in a new 3D culture model : application to the study of Heterocyclic Aromatic Amines (HAAs). [Doctoral Dissertation]. Rennes 1; 2018. Available from: http://www.theses.fr/2018REN1B022

25. Γαλάνη, Εριέττα. Πρωτογενείς καλλιέργειες ανθρωπίνων κυττάρων ήπατος: μελέτη αλληλεπιδράσεων με κύτταρα ανοσοποιητικού συστήματος: παρουσία φλεγμονωδών παραγόντων.

Degree: 2013, National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ)

URL: http://hdl.handle.net/10442/hedi/41744

► The rich blood supply of the liver, approximately 1500ml/min, results in allblood components, including plasma and monocytes, circulating constantly insidethe sinusoids. The dominant aspect today… (more)

▼ The rich blood supply of the liver, approximately 1500ml/min, results in allblood components, including plasma and monocytes, circulating constantly insidethe sinusoids. The dominant aspect today is that there is continuous contactbetween hepatocytes and mononuclear cells through cytoplasmic projections; thiscontact though depends on factors that can change the endothelial fenestrations’diameter, such as the presence of inflammation.Our aim is to investigate the interactions between hepatocytes andhomologous mononuclear cells in vitro, when the two populations are in co‐culturewithout the endothelial barrier and intwo chosen ratios. In the 5:1ratio(hepatocytes/monocytes), which mimics the normal in vivo ratio, the co‐cultureof cell populations has no substantial impact on their viability or activation.However, in the 1:1 ratio which resembles the acute inflammation ratio, theinteractions between cells in respect to their viability and activation, display adifferent pattern. This implies different ratios of contact between cells may beenough to trigger different interactions, even in the absence of an inflammatoryfactor.We then tried to investigate the impact of changing the characteristics ofanother physiological encounter: the encounter of hepatocytes and monocytes withlipopolysaccharide(LPS).Human portal vein LPS blood concentrations range normallyfrom 10pg/ml to1ng/ml. In our experiments we first tested the effect of differentLPS concentrations on monocultures. The addition of LPS led to early reduction ofmean viability and albumin production by hepatocytes, as well as reduction of meanviability and up‐regulation of mean activation of CD4+ and CD8+ cells. The power ofLPS effect was shown to be dose and time dependent in a non‐linear fashion, and itwas also found to be a dynamic phenomenon which takes place in consequent cycles, probably in accordance with different cycles of attachment and detachmentof LPS to its receptors on both cell types. The statistical analysis showed also thatLPS effect on viability and activation is more prominent on CD4+ than CD8+ cells. We finally investigated the effect of LPS on hepatocyte‐monocyte co‐culturesat a ratio of 1:1. The effects of LPS on co‐cultures were found to be similar to thoseobserved in monocultures, they were however more prominent and continuous.In conclusion, the interactions between hepatocytes and monocytes in coculturecan be altered by simply changing the ratio of the co‐culture, which supportsthe fact that hepatocytes and monocytes continuously perceive and respond tominimal changes of their environment. In addition, the effect of different LPSconcentrations has a similar pattern on each cell population, but each sampledisplays a unique behavior which apparently depends on donor immunologicalstatus as well as on other factors not always known or easily controlled even invitro.LPS factor has a cytotoxic effect on hepatocytes and monocytes, but LPSconcentration itself cannot accurately predict the severity of the cytotoxicity and theoverall response of…

Subjects/Keywords: Πρωτογενείς καλλιέργειες; Ανθρώπινα κύτταρα ήπατος; Αλληλεπιδράσεις με κύτταρα ανοσοποιητών; Φλεγμονώδεις παράγοντες; Ομόλογα λεμφοκύτταρα; Ομόλογα μονοπύρηνα; ΛΙΠΟΠΟΛΥΣΑΚΧΑΡΙΤΕΣ; Human hepatocytes; Primary culture; Co - culture; Homologous blood cells; Inflammatory agents; Lipopolysaccharide (LPS); Homologous lymphocytes

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APA (6^th Edition):

Γαλάνη, . �. (2013). Πρωτογενείς καλλιέργειες ανθρωπίνων κυττάρων ήπατος: μελέτη αλληλεπιδράσεων με κύτταρα ανοσοποιητικού συστήματος: παρουσία φλεγμονωδών παραγόντων. (Thesis). National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ). Retrieved from http://hdl.handle.net/10442/hedi/41744

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Γαλάνη, Εριέττα. “Πρωτογενείς καλλιέργειες ανθρωπίνων κυττάρων ήπατος: μελέτη αλληλεπιδράσεων με κύτταρα ανοσοποιητικού συστήματος: παρουσία φλεγμονωδών παραγόντων.” 2013. Thesis, National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ). Accessed January 18, 2021. http://hdl.handle.net/10442/hedi/41744.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Γαλάνη, Εριέττα. “Πρωτογενείς καλλιέργειες ανθρωπίνων κυττάρων ήπατος: μελέτη αλληλεπιδράσεων με κύτταρα ανοσοποιητικού συστήματος: παρουσία φλεγμονωδών παραγόντων.” 2013. Web. 18 Jan 2021.

Vancouver:

Γαλάνη �. Πρωτογενείς καλλιέργειες ανθρωπίνων κυττάρων ήπατος: μελέτη αλληλεπιδράσεων με κύτταρα ανοσοποιητικού συστήματος: παρουσία φλεγμονωδών παραγόντων. [Internet] [Thesis]. National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ); 2013. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/10442/hedi/41744.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Γαλάνη �. Πρωτογενείς καλλιέργειες ανθρωπίνων κυττάρων ήπατος: μελέτη αλληλεπιδράσεων με κύτταρα ανοσοποιητικού συστήματος: παρουσία φλεγμονωδών παραγόντων. [Thesis]. National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ); 2013. Available from: http://hdl.handle.net/10442/hedi/41744

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Université Paris-Sud – Paris XI

26. Corbineau, Sébastien. Génération de progéniteurs hépatiques dérivés de cellules souches : application à l’hypercholestérolémie familiale : Generation of stem cell-derived hepatic progenitors : application to familial hypercholesterolaemia.

Degree: Docteur es, Physiopathologie cellulaire et moléculaire, 2011, Université Paris-Sud – Paris XI

URL: http://www.theses.fr/2011PA114821

►

La transplantation d’hépatocytes représente une alternative à la transplantation hépatique pour le traitement de certaines maladies métaboliques dont l’hypercholestérolémie familiale. Les cellules souches embryonnaires (ES)… (more)

Subjects/Keywords: Cellules souches pluripotentes induites; Primate non humain; Hypercholestérolémie familiale; Humain; Récepteur aux low density lipoproteins; Criblage thérapeutique; Thérapie génique ex vivo; Liver; Hepatocytes; Embryonic stem cells; Induced pluripotent stem cells; Developement; Differentiation; Human/ primate; Familial hypercholesterolaemia; Low density lipoproteins receptor; Therapeutic screening; Ex vivo gene therapy

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Corbineau, S. (2011). Génération de progéniteurs hépatiques dérivés de cellules souches : application à l’hypercholestérolémie familiale : Generation of stem cell-derived hepatic progenitors : application to familial hypercholesterolaemia. (Doctoral Dissertation). Université Paris-Sud – Paris XI. Retrieved from http://www.theses.fr/2011PA114821

Chicago Manual of Style (16^th Edition):

Corbineau, Sébastien. “Génération de progéniteurs hépatiques dérivés de cellules souches : application à l’hypercholestérolémie familiale : Generation of stem cell-derived hepatic progenitors : application to familial hypercholesterolaemia.” 2011. Doctoral Dissertation, Université Paris-Sud – Paris XI. Accessed January 18, 2021. http://www.theses.fr/2011PA114821.

MLA Handbook (7^th Edition):

Corbineau, Sébastien. “Génération de progéniteurs hépatiques dérivés de cellules souches : application à l’hypercholestérolémie familiale : Generation of stem cell-derived hepatic progenitors : application to familial hypercholesterolaemia.” 2011. Web. 18 Jan 2021.

Vancouver:

Corbineau S. Génération de progéniteurs hépatiques dérivés de cellules souches : application à l’hypercholestérolémie familiale : Generation of stem cell-derived hepatic progenitors : application to familial hypercholesterolaemia. [Internet] [Doctoral dissertation]. Université Paris-Sud – Paris XI; 2011. [cited 2021 Jan 18]. Available from: http://www.theses.fr/2011PA114821.

Council of Science Editors:

Corbineau S. Génération de progéniteurs hépatiques dérivés de cellules souches : application à l’hypercholestérolémie familiale : Generation of stem cell-derived hepatic progenitors : application to familial hypercholesterolaemia. [Doctoral Dissertation]. Université Paris-Sud – Paris XI; 2011. Available from: http://www.theses.fr/2011PA114821

Freie Universität Berlin

27. Vondran, Florian Wolfgang Rudolf. Optimization of the isolation and cryopreservation of primary human hepatocytes.

Degree: 2008, Freie Universität Berlin

URL: http://dx.doi.org/10.17169/refubium-10510

► Primary human hepatocytes represent a valuable tool used in basic research and pharmacotoxicology. Hepatocytes of high quality and quantity are required, but supply is limited… (more)

▼ Primary human hepatocytes represent a valuable tool used in basic research and pharmacotoxicology. Hepatocytes of high quality and quantity are required, but supply is limited by the small number of adequate cell sources. In order to optimize cell availability, the present study investigates the influence of donor liver characteristics on the outcome of hepatocyte isolation from surgically removed liver tissue. Furthermore, the benefit of the disaccharide trehalose on the cryopreservation of primary human hepatocytes is examined. Applying standardized tissue procurement, hepatocytes were isolated from small liver samples (10-51g) using a standardized 2-step-collagenase perfusion technique. No significant influence was observed for the tissue donor´s sex, pre-operative blood parameters, previous chemotherapy or histopathology. Donor age significantly influences the isolation outcome, but as a single parameter, was not found suitable for predicting cell yields. The indication for surgery also significantly affects the isolation outcome. Tissues from donors with benign liver diseases are the most yielding, followed by specimens removed during hepatectomy for secondary and primary tumors, respectively. The indication for surgery is a valuable basis for identifying the specimens with the best expectation concerning the isolation outcome. In addition, we observed that the pre-operative serum level of gamma-glutamytransferase seems to affect the cell function of the freshly isolated hepatocytes. Liver cells from donors with GGT levels >60 U/l showed reduced cell viability, total protein level and albumin production. In order to optimize the cryopreservation outcome, primary human hepatocytes were frozen in culture medium containing 10% DMSO supplemented with varying concentrations of trehalose. Upon thawing of the hepatocytes, cell viability, plating efficiency, total protein, cell proliferation, enzyme leakage, albumin and urea formation as well as phase I and II metabolism were analyzed. Among the concentrations investigated, 0.2 M trehalose showed the best overall outcome. Compared to the single use of DMSO, we found significant improvement in post- thaw cell viability (62.9 ± 13 vs. 46.9 ± 11 %, p < 0.01) and plating efficiency (41.5 ± 18 vs. 17.6 ± 13 %, p < 0.01) in the trehalose group. The use of trehalose as an additional cryoprotective agent resulted in a significantly increased total protein level, higher secretion of albumin and a lower AST level after thawing. The combined application of DMSO and trehalose significantly improves the outcome of human hepatocyte cryopreservation. Advisors/Committee Members: n (gender), Prof. Dr. med. P. Neuhaus (firstReferee), Prof. Dr. med. Th. Steinmüller (furtherReferee), Prof. Dr. med. H. Lang (furtherReferee).

Subjects/Keywords: isolation; cryopreservation; primary human hepatocytes; donor characteristics; trehalose; 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Vondran, F. W. R. (2008). Optimization of the isolation and cryopreservation of primary human hepatocytes. (Thesis). Freie Universität Berlin. Retrieved from http://dx.doi.org/10.17169/refubium-10510

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Vondran, Florian Wolfgang Rudolf. “Optimization of the isolation and cryopreservation of primary human hepatocytes.” 2008. Thesis, Freie Universität Berlin. Accessed January 18, 2021. http://dx.doi.org/10.17169/refubium-10510.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Vondran, Florian Wolfgang Rudolf. “Optimization of the isolation and cryopreservation of primary human hepatocytes.” 2008. Web. 18 Jan 2021.

Vancouver:

Vondran FWR. Optimization of the isolation and cryopreservation of primary human hepatocytes. [Internet] [Thesis]. Freie Universität Berlin; 2008. [cited 2021 Jan 18]. Available from: http://dx.doi.org/10.17169/refubium-10510.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Vondran FWR. Optimization of the isolation and cryopreservation of primary human hepatocytes. [Thesis]. Freie Universität Berlin; 2008. Available from: http://dx.doi.org/10.17169/refubium-10510

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

28. Holmgren, Gustav. In vitro toxicity testing using human pluripotent stem cell derivatives.

Degree: 2016, University of Gothenburg / Göteborgs Universitet

URL: http://hdl.handle.net/2077/47401

► Toxicity testing of chemicals, drug candidates, and food additives is in need of a change. The present methods, mainly consisting of animal models with their… (more)

▼ Toxicity testing of chemicals, drug candidates, and food additives is in need of a change. The present methods, mainly consisting of animal models with their associated ethical concerns, are expensive, time-consuming, and importantly they are often poor predictors of the human in vivo toxicity. With the rapid biotechnology development, a paradigm shift for toxicity testing is emerging, focusing on bioinformatics, computational toxicity, systems biology, and cell-based in vitro models. The aim of this thesis was to investigate the utility of using cells, i.e. hepatocytes and cardiomyocytes, derived from human pluripotent stem cells (hPSC) as in vitro models for toxicity testing. The first part explored the feasibility of using hPSC-derived hepatocytes to study toxic drug exposure, and in addition investigated the relevancy of the cellular response. The second and major part of this thesis focused on hPSC-derived cardiomyocytes and the in-depth study of doxorubicin-induced toxicity. The studies revealed that the differentiation processes and culturing of hPSC-derivatives are stable and reproducible to form the basis for in vitro models for toxicity testing, even for longer studies over two weeks. The hepatocytes and the cardiomyocytes showed sensitivity towards the toxic compounds and both cell models dis-played a relevant cellular response to the toxic exposure. For example, the hepatocytes showed evidence of steatosis and phospholipidosis when incubated with hepatotoxic compounds over time. Besides an evident effect of doxorubicin on the cardiomyocyte function, the cells also proved to be useful for more in-depth mechanistic evaluations, as these studies gave insight, on multiple biological levels, in plausible mechanisms and identified potential biomarkers for doxorubicin-induced cardiotoxicity. In conclusion, this thesis presents findings that supports the vision and strategy of using in vitro models based on hPSC-derivatives together with advanced omics technologies for toxicity testing and risk assessment of drugs, food additives, and chemicals.

Subjects/Keywords: toxicity testing; human pluripotent stem cells; cardiomyocytes; hepatocytes; microarray; quantitative proteomics; bioinformatics; transcriptomics; microRNA

…chronic toxicity testing using human pluripotent stem cellderived hepatocytes Drug Metab Dispos… …derived hepatocytes hPSC human pluripotent stem cells InCroMAP Integrated analysis of Cross… …analysis PHH Primary human hepatocytes RNA Ribonucleic acid SAM Significance analysis of… …studies are primary human hepatocytes (PHH). However, the shortage of appropriate… …doxorubicin-induced toxicity in human cardiomyocytes derived from pluripotent stem cells Toxicology…

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Holmgren, G. (2016). In vitro toxicity testing using human pluripotent stem cell derivatives. (Thesis). University of Gothenburg / Göteborgs Universitet. Retrieved from http://hdl.handle.net/2077/47401

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Holmgren, Gustav. “In vitro toxicity testing using human pluripotent stem cell derivatives.” 2016. Thesis, University of Gothenburg / Göteborgs Universitet. Accessed January 18, 2021. http://hdl.handle.net/2077/47401.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Holmgren, Gustav. “In vitro toxicity testing using human pluripotent stem cell derivatives.” 2016. Web. 18 Jan 2021.

Vancouver:

Holmgren G. In vitro toxicity testing using human pluripotent stem cell derivatives. [Internet] [Thesis]. University of Gothenburg / Göteborgs Universitet; 2016. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/2077/47401.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Holmgren G. In vitro toxicity testing using human pluripotent stem cell derivatives. [Thesis]. University of Gothenburg / Göteborgs Universitet; 2016. Available from: http://hdl.handle.net/2077/47401

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

29. Ghosheh, Nidal. Methylome and Transcriptome Profiling of Hepatocytes Derived from Human Pluripotent Stem Cells.

Degree: 2018, University of Gothenburg / Göteborgs Universitet

URL: http://hdl.handle.net/2077/54951

► Six hundred million people suffering from liver diseases worldwide of which the lethality is two million. Freshly isolated hepatocytes from the liver have been used… (more)

Subjects/Keywords: human pluripotent stem cells; gene transcription; gene regulation; DNA methylation; transcriptome; hepatocytes

…involved in hepatic functionality in human pluripotent stem cell-derived hepatocytes… …hepatocytes HiPSC Human-induced pluripotent stem cells HPSC Human pluripotent stem cells HPSC… …Derived from Human Pluripotent Stem Cells included hepatocytes in the device compensate for… …biotransformation and synthetic functions of the liver. Primary human hepatocytes, porcine hepatocytes… …while 7 Methylome and Transcriptome Profiling of Hepatocytes Derived from Human Pluripotent…

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ghosheh, N. (2018). Methylome and Transcriptome Profiling of Hepatocytes Derived from Human Pluripotent Stem Cells. (Thesis). University of Gothenburg / Göteborgs Universitet. Retrieved from http://hdl.handle.net/2077/54951

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Ghosheh, Nidal. “Methylome and Transcriptome Profiling of Hepatocytes Derived from Human Pluripotent Stem Cells.” 2018. Thesis, University of Gothenburg / Göteborgs Universitet. Accessed January 18, 2021. http://hdl.handle.net/2077/54951.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Ghosheh, Nidal. “Methylome and Transcriptome Profiling of Hepatocytes Derived from Human Pluripotent Stem Cells.” 2018. Web. 18 Jan 2021.

Vancouver:

Ghosheh N. Methylome and Transcriptome Profiling of Hepatocytes Derived from Human Pluripotent Stem Cells. [Internet] [Thesis]. University of Gothenburg / Göteborgs Universitet; 2018. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/2077/54951.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Ghosheh N. Methylome and Transcriptome Profiling of Hepatocytes Derived from Human Pluripotent Stem Cells. [Thesis]. University of Gothenburg / Göteborgs Universitet; 2018. Available from: http://hdl.handle.net/2077/54951

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Queensland University of Technology

30. Swagell, Christopher Dean. Molecular markers of obesity and diabetes.

Degree: 2007, Queensland University of Technology

URL: https://eprints.qut.edu.au/35762/

► Recently it has been shown that the consumption of a diet high in saturated fat is associated with impaired insulin sensitivity and increased incidence of… (more)

▼ Recently it has been shown that the consumption of a diet high in saturated fat is associated with impaired insulin sensitivity and increased incidence of type 2 diabetes. In contrast, diets that are high in monounsaturated fatty acids (MUFAs) or polyunsaturated fatty acids (PUFAs), especially very long chain n-3 fatty acids (FAs), are protective against disease. However, the molecular mechanisms by which saturated FAs induce the insulin resistance and hyperglycaemia associated with metabolic syndrome and type 2 diabetes are not clearly defined. It is possible that saturated FAs may act through alternative mechanisms compared to MUFA and PUFA to regulate of hepatic gene expression and metabolism. It is proposed that, like MUFA and PUFA, saturated FAs regulate the transcription of target genes. To test this hypothesis, hepatic gene expression analysis was undertaken in a human hepatoma cell line, Huh-7, after exposure to the saturated FA, palmitate. These experiments showed that palmitate is an effective regulator of gene expression for a wide variety of genes. A total of 162 genes were differentially expressed in response to palmitate. These changes not only affected the expression of genes related to nutrient transport and metabolism, they also extend to other cellular functions including, cytoskeletal architecture, cell growth, protein synthesis and oxidative stress response. In addition, this thesis has shown that palmitate exposure altered the expression patterns of several genes that have previously been identified in the literature as markers of risk of disease development, including CVD, hypertension, obesity and type 2 diabetes. The altered gene expression patterns associated with an increased risk of disease include apolipoprotein-B100 (apo-B100), apo-CIII, plasminogen activator inhibitor 1, insulin-like growth factor-I and insulin-like growth factor binding protein 3. This thesis reports the first observation that palmitate directly signals in cultured human hepatocytes to regulate expression of genes involved in energy metabolism as well as other important genes. Prolonged exposure to long-chain saturated FAs reduces glucose phosphorylation and glycogen synthesis in the liver. Decreased glucose metabolism leads to elevated rates of lipolysis, resulting in increased release of free FAs. Free FAs have a negative effect on insulin action on the liver, which in turn results in increased gluconeogenesis and systemic dyslipidaemia. It has been postulated that disruption of glucose transport and insulin secretion by prolonged excessive FA availability might be a non-genetic factor that has contributed to the staggering rise in prevalence of type 2 diabetes. As glucokinase (GK) is a key regulatory enzyme of hepatic glucose metabolism, changes in its activity may alter flux through the glycolytic and de novo lipogenic pathways and result in hyperglycaemia and ultimately insulin resistance. This thesis investigated the effects of saturated FA on the promoter activity of the glycolytic enzyme,…

Subjects/Keywords: cDNA microarray analysis, gene expression, saturated fatty acid, palmitate, hepatocytes, glucokinase, microarray analysis, monounsaturated fatty acid, polyunsaturated fatty acid, oleate, eicosapentaenoic acid, human hepatic cell line; fatty acid signalling, fatty acids, glycolysis, insulin, primary rat hepatocytes

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Swagell, C. D. (2007). Molecular markers of obesity and diabetes. (Thesis). Queensland University of Technology. Retrieved from https://eprints.qut.edu.au/35762/

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Swagell, Christopher Dean. “Molecular markers of obesity and diabetes.” 2007. Thesis, Queensland University of Technology. Accessed January 18, 2021. https://eprints.qut.edu.au/35762/.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Swagell, Christopher Dean. “Molecular markers of obesity and diabetes.” 2007. Web. 18 Jan 2021.

Vancouver:

Swagell CD. Molecular markers of obesity and diabetes. [Internet] [Thesis]. Queensland University of Technology; 2007. [cited 2021 Jan 18]. Available from: https://eprints.qut.edu.au/35762/.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Swagell CD. Molecular markers of obesity and diabetes. [Thesis]. Queensland University of Technology; 2007. Available from: https://eprints.qut.edu.au/35762/

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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Open Access Theses and Dissertations