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McMaster University
1.
Mitchell, Ryan.
OCT4 Facilitated Alteration of Human Cell Fate.
Degree: PhD, 2015, McMaster University
URL: http://hdl.handle.net/11375/18114 
► OCT4 is one of four transcription factors known to induce pluripotency when expressed together in somatic cells. However, brief expression of these pluripotency inducing factors…
(more)
▼ OCT4 is one of four transcription factors known to induce pluripotency when expressed together in somatic cells. However, brief expression of these pluripotency inducing factors in somatic skin fibroblasts followed by treatment with lineage specific culture conditions results in direct conversion towards alternative lineage specific cell types. Our group has previously shown that expression of OCT4 alone in adult human fibroblasts followed by treatment with hematopoietic supportive conditions resulted in the generation of multi-potent blood progenitors without transitioning through a pluripotent intermediate. Despite never having been associated with transcriptional regulation within the hematopoietic compartment, expression of OCT4 induced expression of hematopoietic factors in skin fibroblasts. As such, I hypothesized that ectopic expression of OCT4 in human somatic cells can induce changes in transcription that bestow the potential to make cell fate choices in response to external stimuli.
In direct support of this notion, we revealed that expression of OCT4 in adult human fibroblasts, followed by culturing in neural supportive conditions resulted in the generation of tri-potent neural progenitors, suggesting the effects of OCT4 were not specific or limited to activation of hematopoietic programs. In an effort to understand how OCT4 bestows the potential to make cell fate choices, we assessed the individual vs combined impact of OCT4 and the extracellular environment on transcription during direct conversion of fibroblasts to both blood and neural progenitors. In doing so, we have started to define an induced state of transcriptional activity that is distinct from cells transitioning to pluripotency, and instead characterized by expression related to lineage
iii
PhD Thesis – RR Mitchell McMaster University - Biochemistry
development that is responsive to changes in the extracellular environment that we have termed OCT4 induced plasticity (OiP). Moreover, we revealed that OCT4 mediated direct conversion can facilitate the reprogramming of hematopoietic progenitor cells towards neural progenitor cells, suggesting that this cellular reprogramming approach is not limited to the use of differentiated fibroblasts. In summary, this thesis expands our current knowledge on both the use and understanding of OCT4 as a facilitator of cellular reprogramming in human somatic cells.
Thesis
Doctor of Philosophy (PhD)
Advisors/Committee Members: Bhatia, Mickie, Biochemistry and Biomedical Sciences.
Subjects/Keywords: Reprogramming
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APA (6th Edition):
Mitchell, R. (2015). OCT4 Facilitated Alteration of Human Cell Fate. (Doctoral Dissertation). McMaster University. Retrieved from http://hdl.handle.net/11375/18114
Chicago Manual of Style (16th Edition):
Mitchell, Ryan. “OCT4 Facilitated Alteration of Human Cell Fate.” 2015. Doctoral Dissertation, McMaster University. Accessed August 22, 2019.
http://hdl.handle.net/11375/18114.
MLA Handbook (7th Edition):
Mitchell, Ryan. “OCT4 Facilitated Alteration of Human Cell Fate.” 2015. Web. 22 Aug 2019.
Vancouver:
Mitchell R. OCT4 Facilitated Alteration of Human Cell Fate. [Internet] [Doctoral dissertation]. McMaster University; 2015. [cited 2019 Aug 22].
Available from: http://hdl.handle.net/11375/18114.
Council of Science Editors:
Mitchell R. OCT4 Facilitated Alteration of Human Cell Fate. [Doctoral Dissertation]. McMaster University; 2015. Available from: http://hdl.handle.net/11375/18114
University of Waikato
2.
Sowry, Blair Gavin.
Epigenetic reprogramming of somatic cells by zygotic factors
.
Degree: 2009, University of Waikato
URL: http://hdl.handle.net/10289/3260
► Cloning cattle using somatic cell nuclear transfer (SCNT) is an inefficient process, with approximately only 5% of transferred embryos developing to live offspring. SCNT produced…
(more)
▼ Cloning cattle using somatic cell nuclear transfer (SCNT) is an inefficient process, with approximately only 5% of transferred embryos developing to live offspring. SCNT produced cattle have a high mortality rate due to a number of developmental abnormalities caused mainly by the incorrect epigenetic reprogramming of the donor cell to a pluripotent state. Conventional bovine SCNT involves fusion of a somatic donor cell into an enucleated metaphase II (MII) arrested oocyte. The resulting embryo is cultured to the blastocyst stage before being transferred to a surrogate cow to produce live offspring. Zygotes were initially thought to be unsuitable as SCNT recipients in bovine, until it was revealed that using telophase II (TII) zygotes as opposed to MII oocytes results in improved in vivo development. Metaphase zygotes have also been used successfully as SCNT recipients in mouse to produce cloned blastocysts and it has been proposed that reprogramming factors sequester in the pronuclei of interphase zygotes. Little is known about the nature the nuclear reprogramming, however a few candidate reprogramming factors have emerged recently. TCTP is known to activate key pluripotency genes (POU5F1 and NANOG) in somatic cell nuclei. It has also been identified as present in bovine oocytes with a high potential to reprogram somatic cells. Reprogramming of cell nuclei by Xenopus egg extract has found to require BRG1. Immunodepletion of BRG1 was shown to decrease the reprogramming ability of the egg extract, whist its over-expression increased reprogramming potential. HDAC1 has been found to initiate a transcriptionally repressive state in preimplantation mouse embryos possibly inhibiting transcription of reprogramming factors. Knockdown of HDAC1 using TSA is known to increase development of mouse NT embryos.
The aim of this study was to produce blastocysts using metaphase zygotes as recipients for SCNT in bovine. In addition, localisation and abundance of candidate reprogramming factors TCTP (TPT1 gene), BRG1 and HDAC1 were examined in MII oocytes as well as TII, interphase and metaphase zygotes.
This study found metaphase zygotes are unsuitable as recipients for bovine SCNT using current methodologies, possibly due to the premature cleavage of the embryos. Control embryos produced using MII oocytes as recipients developed to blastocyst with an efficiency of ~ 11%. mRNA analysis of zygotes and oocytes did not reveal any significant differences in the relative concentrations of TPT1 or BRG1 between the samples. The TCTP and HDAC1 proteins showed a similar pattern of localisation in the MII oocytes and all stages of zygotes. Both proteins clearly localise to the maternal chromatin in the second polar body of TII zygotes. This finding has never previously been described and may in part explain why there is increased cloning efficiency observed when using TII zygotes as SCNT recipients.
This increased understanding of these reprogramming factors may increase our knowledge of the processes which occur during NT and lead to greater…
Subjects/Keywords: Reprogramming;
Cloning
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APA (6th Edition):
Sowry, B. G. (2009). Epigenetic reprogramming of somatic cells by zygotic factors
. (Masters Thesis). University of Waikato. Retrieved from http://hdl.handle.net/10289/3260
Chicago Manual of Style (16th Edition):
Sowry, Blair Gavin. “Epigenetic reprogramming of somatic cells by zygotic factors
.” 2009. Masters Thesis, University of Waikato. Accessed August 22, 2019.
http://hdl.handle.net/10289/3260.
MLA Handbook (7th Edition):
Sowry, Blair Gavin. “Epigenetic reprogramming of somatic cells by zygotic factors
.” 2009. Web. 22 Aug 2019.
Vancouver:
Sowry BG. Epigenetic reprogramming of somatic cells by zygotic factors
. [Internet] [Masters thesis]. University of Waikato; 2009. [cited 2019 Aug 22].
Available from: http://hdl.handle.net/10289/3260.
Council of Science Editors:
Sowry BG. Epigenetic reprogramming of somatic cells by zygotic factors
. [Masters Thesis]. University of Waikato; 2009. Available from: http://hdl.handle.net/10289/3260
3.
Papathanasiou, Maria.
Μελέτες των μηχανισμών του κυτταρικού επαναπρογραμματισμού σε εμβρυονικούς ινοβλάστες ποντικού.
Degree: 2018, National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ)
URL: http://hdl.handle.net/10442/hedi/44046
► The generation of induced pluripotent stem cells (iPSCs) by the co-expression of OSKM (Oct4, Sox2, Klf4 and c-Myc) is a prolonged, asynchronous and inefficient process…
(more)
▼ The generation of induced pluripotent stem cells (iPSCs) by the co-expression of OSKM (Oct4, Sox2, Klf4 and c-Myc) is a prolonged, asynchronous and inefficient process of many intermediate stages and molecular obstacles. In order to understand the dynamic nature of reprogramming, it’s highly required both the identification and characterization of transcriptional regulators that drive different cell types to pluripotency. We reprogrammed Mouse Embryonic Fibroblasts (MEFs) and mouse Hepatocytes (mHeps) upon OSKM lentiviral transduction and we discovered that cellular reprogramming occurs through two “waves” of transcriptional changes and identified a gene regulatory network composed of 9 Transcriptional Regulators (TRs; Cbfa2t3, Gli2, Irf6, Nanog, Ovol1, Rcan1, Taf1c, Tead4 and Tfap4), which are directly targeted by OSKM. Single-cell gene expression experiments revealed that the 9 TRs are (co)-expressed in a remarkably small number of cells, the pre-iPSCs colonies. These results can explain the low percentage of reprogrammed cells and the dual nature of cellular reprogramming (stochastic and deterministic). ChIP-seq experiments for the OSKM genomic DNA binding and distribution in different timepoints of the process revealed that the dynamic OSKM DNA binding causes a strong chromatin reorganization, where Oct4 pre-marks Sox2, Klf4 and Myc binding sites. Thus, the prime OSKM DNA binding and the subsequent stochastic co-expression of 9 TRs in a specific subset of reprogrammed cells induce the reconstruction of a gene regulatory network crucial for the generation of iPSCs.
Ο κυτταρικός επαναπρογραμματισμός για τη δημιουργία επαγόμενων πολυδύ-ναμων βλαστοκυττάρων (iPSCs), μέσω της ταυτόχρονης υπερέκφρασης των Oct4, Sox2, Klf4 και c-Myc (OSKM) μεταγραφικών ρυθμιστών, είναι μία χρονοβόρα, ασύγχρονη και μη αποτελεσματική διαδικασία που περιλαμβάνει αρκετά ενδιάμεσα στάδια και χαρακτηρίζεται από την ύπαρξη μεγάλου αριθμού μοριακών εμποδίων τα οποία θα πρέπει να ξεπεραστούν. Για να μελετήσουμε τη δυναμική φύση αυτής της διαδικασίας, είναι απαραίτητο όχι μόνο να ταυτοποιηθούν, αλλά και να χαρακτηριστούν οι μεταγραφικοί ρυθμιστές που καθοδηγούν τη διαδικασία έτσι ώστε διαφορετικοί κυτταρικοί τύποι να μεταβούν σε κατάσταση πολυδυναμικότητας. Επαναπρογραμματίσαμε εμβρυονικούς ινοβλάστες (MEFs) και ηπατοκύτταρα ποντικού (mHeps), με την χρήση κατάλληλης πειραματικής πλατφόρμας, στην οποία χρησιμοποιείται λεντιϊκο σύστημα επαγώμενης γονιδιακής έκφρασης των OSKM. Ανακαλύψαμε ότι η διαδικασία του κυτταρικού επαναπρογραμματισμού περιλαμβάνει δύο διαδοχικά «κύματα» μεταγραφικών αλλαγών και ταυτοποιήσαμε 9 μεταγραφικούς ρυθμιστές (9ΜΡ) οι οποίοι συγκροτούν ένα ρυθμιστικό γονιδιακό δίκτυο, αποτελούν άμεσους στόχους των OSKM και είναι απολύτως απαραίτητοι για τον κυτταρικό επαναπρογραμματισμό και των δύο κυτταρικών τύπων. Τα πειράματα μελέτης του προτύπου έκφρασης των 9ΜΡ σε μοναδιαία κύτταρα, αποκάλυψαν ότι η πλειοψηφία τους (συν)-εκφράζεται επιλεκτικά σε ένα μόνο μικρό αριθμό κυττάρων, τα οποία αποτελούν πρόδρομα κύτταρα iPSCs…
Subjects/Keywords: Eπαναπρογραμματισμός; Reprogramming
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APA (6th Edition):
Papathanasiou, M. (2018). Μελέτες των μηχανισμών του κυτταρικού επαναπρογραμματισμού σε εμβρυονικούς ινοβλάστες ποντικού. (Thesis). National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ). Retrieved from http://hdl.handle.net/10442/hedi/44046
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Papathanasiou, Maria. “Μελέτες των μηχανισμών του κυτταρικού επαναπρογραμματισμού σε εμβρυονικούς ινοβλάστες ποντικού.” 2018. Thesis, National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ). Accessed August 22, 2019.
http://hdl.handle.net/10442/hedi/44046.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Papathanasiou, Maria. “Μελέτες των μηχανισμών του κυτταρικού επαναπρογραμματισμού σε εμβρυονικούς ινοβλάστες ποντικού.” 2018. Web. 22 Aug 2019.
Vancouver:
Papathanasiou M. Μελέτες των μηχανισμών του κυτταρικού επαναπρογραμματισμού σε εμβρυονικούς ινοβλάστες ποντικού. [Internet] [Thesis]. National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ); 2018. [cited 2019 Aug 22].
Available from: http://hdl.handle.net/10442/hedi/44046.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Papathanasiou M. Μελέτες των μηχανισμών του κυτταρικού επαναπρογραμματισμού σε εμβρυονικούς ινοβλάστες ποντικού. [Thesis]. National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ); 2018. Available from: http://hdl.handle.net/10442/hedi/44046
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Southern California
4.
Wei, Zong.
The mechanisms of somatic cell reprogramming.
Degree: PhD, Genetic, Molecular and Cellular Biology, 2012, University of Southern California
URL: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/77661/rec/6976
► The discovery of induced pluripotent stem cells (iPSCs) has transformed the research of stem cells and provided infinite possibilities in regenerative medicine. In classical Yamanaka…
(more)
▼ The discovery of induced pluripotent stem cells
(iPSCs) has transformed the research of stem cells and provided
infinite possibilities in regenerative medicine. In classical
Yamanaka protocol, somatic cells from various sources can be
reprogrammed to iPSCs with forced expression of Oct4, Sox2, Klf4,
and cMyc. Numerous other combinations of factors and various
delivery methods have also been developed to optimize the
efficiency and accustom to different applications. These iPSCs are
useful for disease modeling, toxicology studies and cell therapy.
However, the molecular mechanisms of this transformation remain
largely unclear. The transition from somatic cells to iPSCs
involved comprehensive changes on epigenetic level of the cells
induced by
reprogramming factors.
Reprogramming factor Klf4 can
physically interact with Oct4 and Sox2. These three transcription
factors co-occupy promoters of many pluripotency related genes,
such as endogenous Nanog and Oct4. The physical interactions depend
on the C2H2 zinc fingers in Klf4. Abrogation of these interactions
will lead to failure of
reprogramming due to the inability of
defective complexes in activating key downstream genes. These
results suggest that direct interactions between
reprogramming
factors are essential for initiating key downstream genes. During
reprogramming, nuclear architecture of the cells also experience
dramatic changes. In pluripotent stem cells (PSCs), endogenous Oct4
loci interact with distant regions in cis and in trans. Many of
these long range interactions are specific to PSCs. PSC-specific
interchromosomal interactions are established prior to
transcriptional activation of endogenous Oct4 during
reprogramming.
In PSCs, Oct4-colocalized domains are enriched in active genes and
pluripotency factor binding. Transcription of Oct4 is facilitated
when the Oct4 locus is co-localized with its interchromosomal
partners. Finally, depletion or overexpression of Klf4 causes
changes in interchromosomal interactions prior to loss of Oct4
transcription and PSC differentiation, suggesting that Klf4
regulates interchromosomal interactions independent of its role as
a transcription factor. Together these results reveal two novel
essential factors in facilitating
reprogramming: physical
interactions between
reprogramming factors and nuclear architecture
dynamics.
Advisors/Committee Members: Stallcup, Michael R. (Committee Chair), Lu, Wange (Committee Member), Coetzee, Gerhard (Gerry) A. (Committee Member), Segil, Neil (Committee Member).
Subjects/Keywords: mechanism; molecular; reprogramming
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APA ·
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MLA ·
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APA (6th Edition):
Wei, Z. (2012). The mechanisms of somatic cell reprogramming. (Doctoral Dissertation). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/77661/rec/6976
Chicago Manual of Style (16th Edition):
Wei, Zong. “The mechanisms of somatic cell reprogramming.” 2012. Doctoral Dissertation, University of Southern California. Accessed August 22, 2019.
http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/77661/rec/6976.
MLA Handbook (7th Edition):
Wei, Zong. “The mechanisms of somatic cell reprogramming.” 2012. Web. 22 Aug 2019.
Vancouver:
Wei Z. The mechanisms of somatic cell reprogramming. [Internet] [Doctoral dissertation]. University of Southern California; 2012. [cited 2019 Aug 22].
Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/77661/rec/6976.
Council of Science Editors:
Wei Z. The mechanisms of somatic cell reprogramming. [Doctoral Dissertation]. University of Southern California; 2012. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/77661/rec/6976
University of Minnesota
5.
BELUR, NANDKISHORE RAGHAV.
Direct Reprogramming Of Fibroblasts Into Muscle Or Neural Lineages By Using Single Transcription Factor With Or Without Myod Transactivation Domain.
Degree: MS, Stem Cell Biology, 2014, University of Minnesota
URL: http://hdl.handle.net/11299/182097
► The generation of induced pluripotent stem cells (iPSCs) from somatic cells has opened new doors for regenerative medicine by overcoming the ethical concerns surrounding embryonic…
(more)
▼ The generation of induced pluripotent stem cells (iPSCs) from somatic cells has opened new doors for regenerative medicine by overcoming the ethical concerns surrounding embryonic stem (ES) cell research. However, iPSC technology presents several safety concerns, such as the potential risk of tumor formation, that have caused apprehension for use of iPSCs in humans. One such approach is "direct reprogramming" which can bypass the iPSC or pluripotent stage and obtain tissue-specific cell types from somatic cells. In this study, we examined whether an important transcription factor involved in myogenesis (Pax3) or neurogenesis (NeuroD1) alone can directly reprogram the mouse embryonic fibroblasts (MEFs) into myogenic or neurogenic lineages, respectively. In addition, we created fusion transcription factors (Pax3 or NeuroD1) with the potent MyoD transactivation domain (MDA) that could facilitate radical acceleration of reprogramming into the desired cell type through chromatin modification compared to wild-type factors. Here, we showed that Pax3 can reprogram MEFs towards a myogenic lineage and that MDA-Pax3 further enhances this myogenic reprogramming event. In addition, ectopic expression of NeuroD1 and MDA-NeuroD1 is able to induce neurogenic genes in MEFs, suggesting the partial neurogenic conversion of MEFs. Furthermore, we also showed that the ectopic expression of NeuroD1 but not MDA-NeuroD1 in myoblasts could suppress myogenic differentiation. These data suggest that single gene transduction such as Pax3 or NeuroD1 will become a feasible therapeutic approach for neuro- and muscle degenerative diseases, respectively.
Subjects/Keywords: MEFs; Muscle; reprogramming
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APA (6th Edition):
BELUR, N. R. (2014). Direct Reprogramming Of Fibroblasts Into Muscle Or Neural Lineages By Using Single Transcription Factor With Or Without Myod Transactivation Domain. (Masters Thesis). University of Minnesota. Retrieved from http://hdl.handle.net/11299/182097
Chicago Manual of Style (16th Edition):
BELUR, NANDKISHORE RAGHAV. “Direct Reprogramming Of Fibroblasts Into Muscle Or Neural Lineages By Using Single Transcription Factor With Or Without Myod Transactivation Domain.” 2014. Masters Thesis, University of Minnesota. Accessed August 22, 2019.
http://hdl.handle.net/11299/182097.
MLA Handbook (7th Edition):
BELUR, NANDKISHORE RAGHAV. “Direct Reprogramming Of Fibroblasts Into Muscle Or Neural Lineages By Using Single Transcription Factor With Or Without Myod Transactivation Domain.” 2014. Web. 22 Aug 2019.
Vancouver:
BELUR NR. Direct Reprogramming Of Fibroblasts Into Muscle Or Neural Lineages By Using Single Transcription Factor With Or Without Myod Transactivation Domain. [Internet] [Masters thesis]. University of Minnesota; 2014. [cited 2019 Aug 22].
Available from: http://hdl.handle.net/11299/182097.
Council of Science Editors:
BELUR NR. Direct Reprogramming Of Fibroblasts Into Muscle Or Neural Lineages By Using Single Transcription Factor With Or Without Myod Transactivation Domain. [Masters Thesis]. University of Minnesota; 2014. Available from: http://hdl.handle.net/11299/182097
University of Edinburgh
6.
Bai, Yu.
A novel technique for manipulating cell fate.
Degree: PhD, 2014, University of Edinburgh
URL: http://hdl.handle.net/1842/17860
► The demonstration that simply by introducing four selected proteins it is possible to change mammalian somatic cells from one phenotype to another is providing important…
(more)
▼ The demonstration that simply by introducing four selected proteins it is possible to change mammalian somatic cells from one phenotype to another is providing important new opportunities in medicine. However, this approach has several limitations. In contrast to other methods of changing cell fate such as cloning and cell fusion it is very slow, very inefficient and it is necessary to have identified the key transcription factors. In both cloning and fusion the nucleus is exposed to the cytoplasm of the recipient cell and it is this that changes nuclear function. With the hope of creating the same effect, extracts from cells of the desired cell type have been introduced into candidate cells. This induced some changes in cell function, but did not change cells from one phenotype to another. The aim of this project was to improve methods for the introduction of extract when human skin cells were exposed to extracts of mouse pluripotent stem cells. During early studies, it was noticed that external materials could enter cells spontaneously at a specific stage of cell cycle, metaphase. When cells in metaphase were exposed to cell extracts pluripotent cell-like colonies were formed. These cells expressed markers of pluripotency such as SSEA4 and Tra-1-60 and could form embryoid bodies that would further differentiate to all three germ layers. Unfortunately this protocol was found to be unrepeatable. In subsequent studies the temperature of exposure to extract was raised from 37 °C to 40 °C with the aim of promoting the fluidity of the cell membrane and so enhancing uptake of extract. A new treatment regime was introduced to increase the proportion of cells exposed to extract while in metaphase. A new protease inhibitor was introduced in order to promote persistence of the extract within the cells. Also, a new TLR3 agonist was introduced to enhance chromosome modification. After these modifications were made pluripotent cell-like colonies formed within 14 days of treatment with extract and these colonies were positive for alkaline phosphatase live staining. Further research is required to complete the development of a routine procedure.
Subjects/Keywords: 571.6; cell fate; reprogramming
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APA ·
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APA (6th Edition):
Bai, Y. (2014). A novel technique for manipulating cell fate. (Doctoral Dissertation). University of Edinburgh. Retrieved from http://hdl.handle.net/1842/17860
Chicago Manual of Style (16th Edition):
Bai, Yu. “A novel technique for manipulating cell fate.” 2014. Doctoral Dissertation, University of Edinburgh. Accessed August 22, 2019.
http://hdl.handle.net/1842/17860.
MLA Handbook (7th Edition):
Bai, Yu. “A novel technique for manipulating cell fate.” 2014. Web. 22 Aug 2019.
Vancouver:
Bai Y. A novel technique for manipulating cell fate. [Internet] [Doctoral dissertation]. University of Edinburgh; 2014. [cited 2019 Aug 22].
Available from: http://hdl.handle.net/1842/17860.
Council of Science Editors:
Bai Y. A novel technique for manipulating cell fate. [Doctoral Dissertation]. University of Edinburgh; 2014. Available from: http://hdl.handle.net/1842/17860
University of Bath
7.
O'Neill, Kathy.
Reprogramming hepatocytes into duct-like cells.
Degree: PhD, 2010, University of Bath
URL: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.528369
► Primary hepatocytes maintained in culture progressively down regulate liver-specific genes and lose their characteristic function and morphology. This process, termed dedifferentiation, is a hindrance to…
(more)
▼ Primary hepatocytes maintained in culture progressively down regulate liver-specific genes and lose their characteristic function and morphology. This process, termed dedifferentiation, is a hindrance to in vitro modelling of systems such as xenobiotic metabolism, liver disease and regeneration. However the results presented here demonstrate that dedifferentiated hapatocytes spontaneously induce expression of ductal genes, and therefore represent a useful model of cell reprogramming.
Subjects/Keywords: 571.6; reprogramming; liver; transdifferentiation
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APA ·
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APA (6th Edition):
O'Neill, K. (2010). Reprogramming hepatocytes into duct-like cells. (Doctoral Dissertation). University of Bath. Retrieved from https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.528369
Chicago Manual of Style (16th Edition):
O'Neill, Kathy. “Reprogramming hepatocytes into duct-like cells.” 2010. Doctoral Dissertation, University of Bath. Accessed August 22, 2019.
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.528369.
MLA Handbook (7th Edition):
O'Neill, Kathy. “Reprogramming hepatocytes into duct-like cells.” 2010. Web. 22 Aug 2019.
Vancouver:
O'Neill K. Reprogramming hepatocytes into duct-like cells. [Internet] [Doctoral dissertation]. University of Bath; 2010. [cited 2019 Aug 22].
Available from: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.528369.
Council of Science Editors:
O'Neill K. Reprogramming hepatocytes into duct-like cells. [Doctoral Dissertation]. University of Bath; 2010. Available from: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.528369
Delft University of Technology
8.
Tan, J.
Robust Downstream Communication and Storage for Computational RFIDs:.
Degree: 2015, Delft University of Technology
URL: http://resolver.tudelft.nl/uuid:9070de1a-6b2a-432a-9eea-c60ca9633391
► Computational RFID (CRFID) devices are emerging platforms that can enable perennial computation and sensing by eliminating the need for batteries. Although much research has been…
(more)
▼ Computational RFID (CRFID) devices are emerging platforms that can enable perennial computation and sensing by eliminating the need for batteries. Although much research has been devoted to improving upstream (CRFID to RFID reader) communication rates, the opposite direction has so far been neglected, presumably due to the difficulty of guaranteeing fast and error-free transfer amidst frequent power interruptions of CRFID. With growing interest in the market where CRFIDs are forever-embedded in many structures, it is necessary for this void to be filled. Therefore, we propose Wisent-a robust downstream communication protocol for CRFIDs that operates on top of the legacy UHF RFID communication protocol: EPC C1G2. The novelty of Wisent is its ability to adaptively change the frame length sent by the reader, based on the length throttling mechanism, to minimize the transfer times at varying channel conditions. We present an implementation of Wisent for the WISP 5 and an off-the-shelf RFID reader. Our experiments show that Wisent allows transfer up to 16 times faster than a baseline, non-adaptive shortest frame case, i.e. single word length, at sub-meter distance. As a case study, we show how Wisent enables wireless CRFID
reprogramming, demonstrating the world's first wirelessly reprogrammable (software defined) CRFID.
Advisors/Committee Members: Pawelczak, P..
Subjects/Keywords: RFID; wireless reprogramming; CRFID; downstream
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APA (6th Edition):
Tan, J. (2015). Robust Downstream Communication and Storage for Computational RFIDs:. (Masters Thesis). Delft University of Technology. Retrieved from http://resolver.tudelft.nl/uuid:9070de1a-6b2a-432a-9eea-c60ca9633391
Chicago Manual of Style (16th Edition):
Tan, J. “Robust Downstream Communication and Storage for Computational RFIDs:.” 2015. Masters Thesis, Delft University of Technology. Accessed August 22, 2019.
http://resolver.tudelft.nl/uuid:9070de1a-6b2a-432a-9eea-c60ca9633391.
MLA Handbook (7th Edition):
Tan, J. “Robust Downstream Communication and Storage for Computational RFIDs:.” 2015. Web. 22 Aug 2019.
Vancouver:
Tan J. Robust Downstream Communication and Storage for Computational RFIDs:. [Internet] [Masters thesis]. Delft University of Technology; 2015. [cited 2019 Aug 22].
Available from: http://resolver.tudelft.nl/uuid:9070de1a-6b2a-432a-9eea-c60ca9633391.
Council of Science Editors:
Tan J. Robust Downstream Communication and Storage for Computational RFIDs:. [Masters Thesis]. Delft University of Technology; 2015. Available from: http://resolver.tudelft.nl/uuid:9070de1a-6b2a-432a-9eea-c60ca9633391
9.
ANG HEATHER YIN-KUAN.
DIRECTED REPROGRAMMING OF FIBROBLASTS INTO HEMATOPOIETIC PROGENITORS BY NUCLEAR REGULATORS.
Degree: 2012, National University of Singapore
URL: http://scholarbank.nus.edu.sg/handle/10635/47634
Subjects/Keywords: Reprogramming; Hematopoiesis
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APA (6th Edition):
YIN-KUAN, A. H. (2012). DIRECTED REPROGRAMMING OF FIBROBLASTS INTO HEMATOPOIETIC PROGENITORS BY NUCLEAR REGULATORS. (Thesis). National University of Singapore. Retrieved from http://scholarbank.nus.edu.sg/handle/10635/47634
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
YIN-KUAN, ANG HEATHER. “DIRECTED REPROGRAMMING OF FIBROBLASTS INTO HEMATOPOIETIC PROGENITORS BY NUCLEAR REGULATORS.” 2012. Thesis, National University of Singapore. Accessed August 22, 2019.
http://scholarbank.nus.edu.sg/handle/10635/47634.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
YIN-KUAN, ANG HEATHER. “DIRECTED REPROGRAMMING OF FIBROBLASTS INTO HEMATOPOIETIC PROGENITORS BY NUCLEAR REGULATORS.” 2012. Web. 22 Aug 2019.
Vancouver:
YIN-KUAN AH. DIRECTED REPROGRAMMING OF FIBROBLASTS INTO HEMATOPOIETIC PROGENITORS BY NUCLEAR REGULATORS. [Internet] [Thesis]. National University of Singapore; 2012. [cited 2019 Aug 22].
Available from: http://scholarbank.nus.edu.sg/handle/10635/47634.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
YIN-KUAN AH. DIRECTED REPROGRAMMING OF FIBROBLASTS INTO HEMATOPOIETIC PROGENITORS BY NUCLEAR REGULATORS. [Thesis]. National University of Singapore; 2012. Available from: http://scholarbank.nus.edu.sg/handle/10635/47634
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Tulane University
10.
Murad, Hakm.
Phenotypic Alterations in Cancer Cells Induced by Mechanochemical Disruption.
Degree: 2018, Tulane University
URL: https://digitallibrary.tulane.edu/islandora/object/tulane:83027
► Cancer’s response to mechanical vibration via high-intensity focused ultrasound and disruptive chemical agents (Mechanochemical Disruption) was examined in vitro and in vivo. We demonstrated that…
(more)
▼ Cancer’s response to mechanical vibration via high-intensity focused ultrasound and disruptive chemical agents (Mechanochemical Disruption) was examined in vitro and in vivo. We demonstrated that mechanochemical disruption of cellular structures induced phenotypic alterations in surviving tumor cells that prevented cancer progression. Mechanochemical disruption inhibited uncontrolled proliferation, tumorigenicity, metastatic development, and re-sensitized multiple cancer types to chemical treatment via alterations in protein expression and impediment of pro-survival signaling. Our study identified a novel curative therapeutic approach that can prevent the development of aggressive cancer phenotypes.
1
hakm murad
Advisors/Committee Members: (author), Khismatullin, damir (Thesis advisor), (Thesis advisor), School of Science & Engineering Biomedical Engineering (Degree granting institution).
Subjects/Keywords: focused ultrasound; cancer; cellular reprogramming
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APA (6th Edition):
Murad, H. (2018). Phenotypic Alterations in Cancer Cells Induced by Mechanochemical Disruption. (Thesis). Tulane University. Retrieved from https://digitallibrary.tulane.edu/islandora/object/tulane:83027
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Murad, Hakm. “Phenotypic Alterations in Cancer Cells Induced by Mechanochemical Disruption.” 2018. Thesis, Tulane University. Accessed August 22, 2019.
https://digitallibrary.tulane.edu/islandora/object/tulane:83027.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Murad, Hakm. “Phenotypic Alterations in Cancer Cells Induced by Mechanochemical Disruption.” 2018. Web. 22 Aug 2019.
Vancouver:
Murad H. Phenotypic Alterations in Cancer Cells Induced by Mechanochemical Disruption. [Internet] [Thesis]. Tulane University; 2018. [cited 2019 Aug 22].
Available from: https://digitallibrary.tulane.edu/islandora/object/tulane:83027.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Murad H. Phenotypic Alterations in Cancer Cells Induced by Mechanochemical Disruption. [Thesis]. Tulane University; 2018. Available from: https://digitallibrary.tulane.edu/islandora/object/tulane:83027
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Minnesota
11.
Johnston, Alura Lynn.
Direct reprogramming of mouse embryonic fibroblasts to oligodendrocyte progenitor cells using various transcription factors.
Degree: MS, Stem Cell Biology, 2013, University of Minnesota
URL: http://hdl.handle.net/11299/162361
► Spinal cord injury (SCI) is a debilitating disorder that affects numerous aspects of a person's health. After injury, oligodendrocytes (myelinating glial cells) in the damaged…
(more)
▼ Spinal cord injury (SCI) is a debilitating disorder that affects numerous aspects of a person's health. After injury, oligodendrocytes (myelinating glial cells) in the damaged spinal cord undergo cell death leading to additional loss of function. Transplantation of oligodendrocyte progenitor cells (OPCs) into injured spinal cords has been shown to increase myelination of axons and improve function in animal models of SCI. Differentiation of human embryonic stem cells (ESCs) and induced pluripotent stem cells (IPSCs) has been proposed to generate OPCs for clinical use. However, using hESCs poses ethical issues and IPSC methods take many weeks to produce OPCs. Various groups have proposed that using direct reprogramming will create a faster method for producing OPCs. Using combinations of transcription factors it was initially found that co-expression of exogenous FoxG1, Sox2, and Brn2 in embryonic fibroblasts can produce a tripotent neural cell lineage that gives rise to neurons and glial cells including oligodendrocytes. It was also shown that FoxG1 and Brn2 alone could produce OPCs. Following these findings it was shown that one transcription factor, Sox2 could produce induced neural stem cells that could differentiate into glial cell types. In this project we attempted to create a population of OPCs using these transcription factors by direct reprogramming of Olig2:CreER mT/mG transgenic mouse embryonic fibroblasts.
Subjects/Keywords: Direct reprogramming; Oligodendrocyte; Progenitor
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APA (6th Edition):
Johnston, A. L. (2013). Direct reprogramming of mouse embryonic fibroblasts to oligodendrocyte progenitor cells using various transcription factors. (Masters Thesis). University of Minnesota. Retrieved from http://hdl.handle.net/11299/162361
Chicago Manual of Style (16th Edition):
Johnston, Alura Lynn. “Direct reprogramming of mouse embryonic fibroblasts to oligodendrocyte progenitor cells using various transcription factors.” 2013. Masters Thesis, University of Minnesota. Accessed August 22, 2019.
http://hdl.handle.net/11299/162361.
MLA Handbook (7th Edition):
Johnston, Alura Lynn. “Direct reprogramming of mouse embryonic fibroblasts to oligodendrocyte progenitor cells using various transcription factors.” 2013. Web. 22 Aug 2019.
Vancouver:
Johnston AL. Direct reprogramming of mouse embryonic fibroblasts to oligodendrocyte progenitor cells using various transcription factors. [Internet] [Masters thesis]. University of Minnesota; 2013. [cited 2019 Aug 22].
Available from: http://hdl.handle.net/11299/162361.
Council of Science Editors:
Johnston AL. Direct reprogramming of mouse embryonic fibroblasts to oligodendrocyte progenitor cells using various transcription factors. [Masters Thesis]. University of Minnesota; 2013. Available from: http://hdl.handle.net/11299/162361
Queens University
12.
Shafi, Nasif Bin.
Efficient Over-the-air Remote Reprogramming of Wireless Sensor Networks
.
Degree: Computing, 2011, Queens University
URL: http://hdl.handle.net/1974/6890
► Over-the-air reprogramming is an important aspect of managing large wireless sensor networks. However, reprogramming deployed sensor networks poses significant challenges due to the energy, processing…
(more)
▼ Over-the-air reprogramming is an important aspect of managing large wireless sensor networks. However, reprogramming deployed sensor networks poses significant challenges due to the energy, processing power and memory limitation of sensor nodes. For improved energy efficiency, a reprogramming mechanism should use less transmission and flash writing overhead. Past research has proposed different mechanisms for reprogramming deployed sensor networks. However, all of these mechanisms produce large patches if software modifications involve changing program layouts and shifting global variables. In addition, existing mechanisms use large amounts of external flash and rewrite entire internal flash. In this thesis, we present a differential reprogramming mechanism called QDiff that mitigates the effects of program layout modifications and retains maximum similarity between old and new software using a clone detection mechanism. Moreover, QDiff organizes the global variables in a novel way that eliminates the effect of variable shifting. Our experiments show that QDiff requires near-zero external flash, and significantly lower internal flash rewriting and transmission overhead than leading existing differential reprogramming mechanisms.
Subjects/Keywords: Wireless Sensor Networks; Reprogramming
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APA (6th Edition):
Shafi, N. B. (2011). Efficient Over-the-air Remote Reprogramming of Wireless Sensor Networks
. (Thesis). Queens University. Retrieved from http://hdl.handle.net/1974/6890
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Shafi, Nasif Bin. “Efficient Over-the-air Remote Reprogramming of Wireless Sensor Networks
.” 2011. Thesis, Queens University. Accessed August 22, 2019.
http://hdl.handle.net/1974/6890.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Shafi, Nasif Bin. “Efficient Over-the-air Remote Reprogramming of Wireless Sensor Networks
.” 2011. Web. 22 Aug 2019.
Vancouver:
Shafi NB. Efficient Over-the-air Remote Reprogramming of Wireless Sensor Networks
. [Internet] [Thesis]. Queens University; 2011. [cited 2019 Aug 22].
Available from: http://hdl.handle.net/1974/6890.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Shafi NB. Efficient Over-the-air Remote Reprogramming of Wireless Sensor Networks
. [Thesis]. Queens University; 2011. Available from: http://hdl.handle.net/1974/6890
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
IUPUI
13.
Faruk, MD Omor.
The design and implementation of mobile deluge on Android platform for wireless sensor network reprogramming.
Degree: 2017, IUPUI
URL: http://hdl.handle.net/1805/15109
► Indiana University-Purdue University Indianapolis (IUPUI)
Wireless Sensor Networks (WSN) is being used in various applications including environmental monitoring, site inspection and military. WSN is a…
(more)
▼ Indiana University-Purdue University Indianapolis (IUPUI)
Wireless Sensor Networks (WSN) is being used in various applications including environmental monitoring, site inspection and military. WSN is a distributed network of sensor devices that can be used to monitor temperature, humidity, light and other important metrics. The software that runs on the sensor devices define how the device should operate. In real world WSN deployment, device software update is required to maintain optimal operation. In this thesis, we propose a novel idea of updating the software of the sensor nodes using a mobile device running on Android Operating System. Our implementation builds upon Mobile Deluge with few enhancement which is a method of re-programming WSN with laptop computer. We have evaluated our application performance by lab experiments and in real world deployments of WSN and found the application stable and battery efficient.
Advisors/Committee Members: Liang, Yao, Tuceryan, Mihran, Mukhopadhyay, Snehasis.
Subjects/Keywords: android; mobile deluge; reprogramming; wireless sensor networks; wireless reprogramming
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APA (6th Edition):
Faruk, M. O. (2017). The design and implementation of mobile deluge on Android platform for wireless sensor network reprogramming. (Thesis). IUPUI. Retrieved from http://hdl.handle.net/1805/15109
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Faruk, MD Omor. “The design and implementation of mobile deluge on Android platform for wireless sensor network reprogramming.” 2017. Thesis, IUPUI. Accessed August 22, 2019.
http://hdl.handle.net/1805/15109.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Faruk, MD Omor. “The design and implementation of mobile deluge on Android platform for wireless sensor network reprogramming.” 2017. Web. 22 Aug 2019.
Vancouver:
Faruk MO. The design and implementation of mobile deluge on Android platform for wireless sensor network reprogramming. [Internet] [Thesis]. IUPUI; 2017. [cited 2019 Aug 22].
Available from: http://hdl.handle.net/1805/15109.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Faruk MO. The design and implementation of mobile deluge on Android platform for wireless sensor network reprogramming. [Thesis]. IUPUI; 2017. Available from: http://hdl.handle.net/1805/15109
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Minnesota
14.
Yang, Ying.
Reprogramming of hepatic progenitor cells towards a
beta-cell character using Pdx1, Ngn3 and MafA.
Degree: MS, Stem cell biology, 2012, University of Minnesota
URL: http://purl.umn.edu/160346
► University of Minnesota M.S. thesis. December 2012. Major: Stem cell biology. Advisor: Dr. Jonathan M.W.Slack. 1 computer file (PDF); vi, 54 pages.
The pancreas and…
(more)
▼ University of Minnesota M.S. thesis. December 2012.
Major: Stem cell biology. Advisor: Dr. Jonathan M.W.Slack. 1
computer file (PDF); vi, 54 pages.
The pancreas and liver arises from adjacent areas
in the anterior endoderm of the developing embryo. This close
relatedness underlies the possibility of direct reprogramming of
the liver cells or hepatocytes towards pancreatic beta cells. In
the present study we show that hepatoblasts in undissociated
early-stage liver buds can be reprogrammed towards a beta cell-like
cell fate by ectopic expression of the pancreatic transcription
genes (Pdx1, Ngn3, and MafA) using a polycistronic adenovirus. The
reprogramming happens by 3 days after Ad-PNM transduction.
Dissociated hepatoblasts isolated from different developmental
stages of embryonic livers, which are considered as hepatic
progenitor cells, also could be reprogrammed efficiently by Ad-PNM.
This was associated with approximately 20% (E18) to 70% (E11) of
hepatoblasts expressing insulin and C-Peptide along with a
significant increase in endocrine gene profiles and down-regulation
of liver markers. Moreover the reprogrammed cells were seen to
express GFP when hepatoblasts were isolated from Pdx1-GFP
transgenic mice, indicating transcription of the endogenous Pdx1, a
hallmark for genuine reprogramming. This allowed us to sort the
green fluorescent cells which, upon stimulating with low (2.8mM) or
high (20mM) glucose, failed to show significant glucose-sensitive
insulin release. However, these cells could maintain the blood
glucose levels of diabetic mice at a stable and normal level for
one month after transplantation. In summary, hepatic progenitor
cells, which may possess a similar epigenetic pattern to pancreatic
progenitor cells, can be reprogrammed by overexpressing pancreatic
transcription factors. This may be a promising resource of cell
therapy for diabetes.
Advisors/Committee Members: Dr. Jonathan M.W.Slack.
Subjects/Keywords: Beta cells; Cell reprogramming; Hepatic progenitor cells
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APA ·
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Export
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Manager
APA (6th Edition):
Yang, Y. (2012). Reprogramming of hepatic progenitor cells towards a
beta-cell character using Pdx1, Ngn3 and MafA. (Masters Thesis). University of Minnesota. Retrieved from http://purl.umn.edu/160346
Chicago Manual of Style (16th Edition):
Yang, Ying. “Reprogramming of hepatic progenitor cells towards a
beta-cell character using Pdx1, Ngn3 and MafA.” 2012. Masters Thesis, University of Minnesota. Accessed August 22, 2019.
http://purl.umn.edu/160346.
MLA Handbook (7th Edition):
Yang, Ying. “Reprogramming of hepatic progenitor cells towards a
beta-cell character using Pdx1, Ngn3 and MafA.” 2012. Web. 22 Aug 2019.
Vancouver:
Yang Y. Reprogramming of hepatic progenitor cells towards a
beta-cell character using Pdx1, Ngn3 and MafA. [Internet] [Masters thesis]. University of Minnesota; 2012. [cited 2019 Aug 22].
Available from: http://purl.umn.edu/160346.
Council of Science Editors:
Yang Y. Reprogramming of hepatic progenitor cells towards a
beta-cell character using Pdx1, Ngn3 and MafA. [Masters Thesis]. University of Minnesota; 2012. Available from: http://purl.umn.edu/160346
15.
GLEESON, LAURA ELIZABETH.
Macrophage immunometabolism in the host response to Mycobacterium tuberculosis infection.
Degree: School of Medicine. Discipline of Clinical Medicine, 2017, Trinity College Dublin
URL: http://hdl.handle.net/2262/81723
► Tuberculosis (TB) is the leading infectious disease killer in the world, alongside HIV. Our understanding of the complex host immune response to Mycobacterium tuberculosis (Mtb)…
(more)
▼ Tuberculosis (TB) is the leading infectious disease killer in the world, alongside HIV. Our understanding of the complex host immune response to Mycobacterium tuberculosis (Mtb) remains incomplete, but varied clinical outcomes of infection seen in humans (ranging from death to complete asymptomatic clearance of the bug) suggest that understanding host defence mechanisms may provide new insights and novel approaches to vaccine and treatment development. Integral to the host immune response to infection is the tissue-resident alveolar macrophage (AM), capable of early eradication of the bacillus but, conversely, vulnerable to subversion by the bacillus to be used as a nidus for survival and replication. Specifically, the pro-inflammatory cytokine Interleukin-1? (IL-1?) is essential for its mycobactericidal activity. Recent work in the burgeoning field of immunometabolism has linked TLR-induced changes in intracellular macrophage glucose metabolism ? namely, a shift towards aerobic glycolysis, known as the Warburg effect ? to production of IL-1?. Thus, in this body of work we investigate the metabolic impact of Mtb infection on human macrophage glucose metabolism and examine downstream functional effects of infection-induced metabolic alterations.
The results presented in this body of work offer new insights into the metabolic characteristics of primary human monocyte-derived macrophages (MDM) and primary human AM. We demonstrate infection-induced glycolytic
reprogramming in human and murine macrophages, mediated through TLR2/6 signalling. We find glycolytic
reprogramming to be essential for optimal production of IL1B mRNA at a transcriptional level, with consequent secretion of mature IL-1?. This glycolysis-driven increase in IL-1? leads to upregulation of the eicosanoid Prostaglandin E2 (PGE2) and suppression of the anti-inflammatory cytokine Interleukin-10 (IL-10), with ultimate enhancement of macrophage mycobactericidal activity in both human and murine macrophages. We further demonstrate a similar requirement for glycolytic
reprogramming in Salmonella typhimurium-infected murine macrophages. Pharmacological augmentation of glycolysis using meclizine dihydrochloride enhanced early bacillary clearance by human MDM, suggesting this newly delineated pathway of host defence may warrant exploration in the search for host-directed therapies for TB disease. Finally, we demonstrate reduced baseline metabolic activity and reduced metabolic reserves in macrophages exposed to cigarette smoke. Smoke-exposed macrophages had an attenuated metabolic response to Mtb infection, concurrent with impaired production of IL-1? and PGE2.
This work demonstrates for the first time a functional role for glycolytic
reprogramming in the context of host defence. This novel mechanism of the anti-mycobacterial macrophage response may be targeted for the development of new therapies and vaccines to combat this global pathogen, particularly given our observation of pharmacological manipulation of glycolytic metabolism enhancing macrophage…
Advisors/Committee Members: Joseph m b, Keane.
Subjects/Keywords: Tuberculosis; Immunometabolism; Macrophage; Host defence; Glycolytic reprogramming
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APA (6th Edition):
GLEESON, L. E. (2017). Macrophage immunometabolism in the host response to Mycobacterium tuberculosis infection. (Thesis). Trinity College Dublin. Retrieved from http://hdl.handle.net/2262/81723
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
GLEESON, LAURA ELIZABETH. “Macrophage immunometabolism in the host response to Mycobacterium tuberculosis infection.” 2017. Thesis, Trinity College Dublin. Accessed August 22, 2019.
http://hdl.handle.net/2262/81723.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
GLEESON, LAURA ELIZABETH. “Macrophage immunometabolism in the host response to Mycobacterium tuberculosis infection.” 2017. Web. 22 Aug 2019.
Vancouver:
GLEESON LE. Macrophage immunometabolism in the host response to Mycobacterium tuberculosis infection. [Internet] [Thesis]. Trinity College Dublin; 2017. [cited 2019 Aug 22].
Available from: http://hdl.handle.net/2262/81723.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
GLEESON LE. Macrophage immunometabolism in the host response to Mycobacterium tuberculosis infection. [Thesis]. Trinity College Dublin; 2017. Available from: http://hdl.handle.net/2262/81723
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of California – San Diego
16.
Tsunemoto, Rachel.
Deciphering Transcriptional Control of Neuronal Identity and Diversity Using Direct Reprogramming.
Degree: Neurosciences, 2016, University of California – San Diego
URL: http://www.escholarship.org/uc/item/59k3t2xt
► The mammalian nervous system is comprised of an unknown, but recognizably large, number of diverse neuronal subtypes. Recently, direct reprogramming (also known as transdifferentiation) has…
(more)
▼ The mammalian nervous system is comprised of an unknown, but recognizably large, number of diverse neuronal subtypes. Recently, direct reprogramming (also known as transdifferentiation) has become an established method to rapidly produce “induced” neurons of numerous different subtypes directly from fibroblasts by overexpressing specific combinations of transcription factors and/or microRNAs. This technique not only provides the means to study various neuronal subtype populations that are not easily accessible, particularly in humans, but it also serves as a tool to interrogate the transcriptional codes that regulate neuronal subtype identity and maintenance. Both in vivo studies and direct reprogramming protocols have demonstrated that basic helix-loop-helix (bHLH) and Pit-Oct-Unc (POU) transcription factors can aid in the specification of distinct neuronal subtypes. Therefore, we set out to comprehensively and systematically address whether first, additional bHLH and POU factor pairings could reprogram fibroblasts into functional neurons and second, dissect out the discrete and synergistic roles of these factors in neuronal subtype specification. We discovered over 70 novel pairs of bHLH and POU (and non-POU) transcription factors sufficient to generate candidate induced neurons (iNs) from mouse embryonic fibroblasts. Transcriptomic analysis of 35 of these candidate iN populations revealed gene expression profiles similar to those of endogenous neuronal populations. Additionally, differences between iN populations were observed at both a transcriptional and functional level.
Subjects/Keywords: Neurosciences; Direct Reprogramming; Induced Neurons; Transcription Factors
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APA (6th Edition):
Tsunemoto, R. (2016). Deciphering Transcriptional Control of Neuronal Identity and Diversity Using Direct Reprogramming. (Thesis). University of California – San Diego. Retrieved from http://www.escholarship.org/uc/item/59k3t2xt
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Tsunemoto, Rachel. “Deciphering Transcriptional Control of Neuronal Identity and Diversity Using Direct Reprogramming.” 2016. Thesis, University of California – San Diego. Accessed August 22, 2019.
http://www.escholarship.org/uc/item/59k3t2xt.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Tsunemoto, Rachel. “Deciphering Transcriptional Control of Neuronal Identity and Diversity Using Direct Reprogramming.” 2016. Web. 22 Aug 2019.
Vancouver:
Tsunemoto R. Deciphering Transcriptional Control of Neuronal Identity and Diversity Using Direct Reprogramming. [Internet] [Thesis]. University of California – San Diego; 2016. [cited 2019 Aug 22].
Available from: http://www.escholarship.org/uc/item/59k3t2xt.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Tsunemoto R. Deciphering Transcriptional Control of Neuronal Identity and Diversity Using Direct Reprogramming. [Thesis]. University of California – San Diego; 2016. Available from: http://www.escholarship.org/uc/item/59k3t2xt
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Adelaide
17.
Lin, Ni-Hung.
Reprogramming of human gingival and periodontal ligament fibroblasts to pluripotency with defined factors.
Degree: 2010, University of Adelaide
URL: http://hdl.handle.net/2440/65628
► Background: The use of periodontal stem cells with tissue engineering techniques constitutes an attractive strategy for regenerative periodontal therapy. However, technical difficulties of isolating a…
(more)
▼ Background: The use of periodontal stem cells with tissue engineering techniques constitutes an attractive strategy for regenerative periodontal therapy. However, technical difficulties of isolating a large quantity of these cells and problem of immune rejection in allogeneic transplantation limit their dental clinical usefulness. Recently, several groups have successfully reprogrammed adult cells to pluripotent cells by retroviral transduction with four genes - Oct3/4, Sox2, Klf4 and cMyc. The resultant induced pluripotent stem (iPS) cells have proliferative and developmental potentials comparable to those of embryonic stem (ES) cells. These cells may represent a good stem cell source for regenerative periodontal therapy. As periodontal tissues are easily accessible, it is hypothesised that periodontal fibroblasts may be an alternative cell source for derivation of iPS cells. Objective: The aim of this study was to generate and characterise iPS cells from human adult gingival fibroblasts and periodontal ligament (PDL) fibroblasts. Methods: Gingival and PDL tissues from around extracted human
adult teeth were collected and digested to obtain single cell suspensions of gingival and PDL fibroblasts. The fibroblasts were lentivirally transduced with mouse receptor for retrovirus mSlc7a1, followed by retroviral transduction with four genes (Oct3/4, Sox2, Klf4 and cMyc). Six days after retroviral transduction, the fibroblasts were re-plated onto mouse embryonic feeders and maintained with daily medium change. At day 25-30, human ES cell-like colonies were harvested for characterisation assays to assess their self-renewal and developmental capacities. Results: Human ES cell-like colonies were observed 25 days after transduction. Cells from these colonies were morphologically similar to human ES cells, expressed ES cell genes assayed by immunostaining and real-time reverse-transcription polymerase chain reaction, showed silencing of exogenous retroviral genes and displayed a normal karyotype. In vitro, these cells formed embryoid bodies with down-regulated expression of ES cell genes and up-regulated expression of ectodermal, mesodermal and endodermal markers. Conclusion: iPS-like cells can be generated from human adult gingival and PDL fibroblasts, and gingival fibroblasts can represent an easily accessible source of cells to derive individual-specific iPS cells for regenerative periodontal therapy.
Advisors/Committee Members: Bartold, Mark (advisor), Gronthos, Stan (advisor), School of Dentistry (school).
Subjects/Keywords: reprogramming; gingival fibroblasts; periodental ligament fibroblasts; pluripotency
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APA (6th Edition):
Lin, N. (2010). Reprogramming of human gingival and periodontal ligament fibroblasts to pluripotency with defined factors. (Thesis). University of Adelaide. Retrieved from http://hdl.handle.net/2440/65628
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Lin, Ni-Hung. “Reprogramming of human gingival and periodontal ligament fibroblasts to pluripotency with defined factors.” 2010. Thesis, University of Adelaide. Accessed August 22, 2019.
http://hdl.handle.net/2440/65628.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Lin, Ni-Hung. “Reprogramming of human gingival and periodontal ligament fibroblasts to pluripotency with defined factors.” 2010. Web. 22 Aug 2019.
Vancouver:
Lin N. Reprogramming of human gingival and periodontal ligament fibroblasts to pluripotency with defined factors. [Internet] [Thesis]. University of Adelaide; 2010. [cited 2019 Aug 22].
Available from: http://hdl.handle.net/2440/65628.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Lin N. Reprogramming of human gingival and periodontal ligament fibroblasts to pluripotency with defined factors. [Thesis]. University of Adelaide; 2010. Available from: http://hdl.handle.net/2440/65628
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Cincinnati
18.
Rao Venkata, Lakshmi Prakruthi.
Epigenetic Reprogramming at the Th2 Locus.
Degree: MS, Medicine: Immunology, 2018, University of Cincinnati
URL: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1543838686940608
► Background and Aims:Atopic diseases are characterized by increased proliferation of T cells and an increase in levels of Th2 cytokines. Memory T cells are capable…
(more)
▼ Background and Aims:Atopic diseases are characterized
by increased proliferation of T cells and an increase in levels of
Th2 cytokines. Memory T cells are capable of producing cytokines
much faster than naive T cells, upon exposure to antigen. This
ability of memory T cells correlates to the presence of positive
histone marks at the cytokine gene loci. This suggests that histone
modifications play a major role in the poising of genes for
transcriptional activity and hence, they can influence the
expression levels of genes. We hypothesize that by targeting the
histone modifications at the Th2 cytokine locus, we can regulate
the expression of the cytokines that play a role in atopic disease
progression.Methods:We have designed plasmids with TALE
(transcription Activator-like Effector) DNA binding domains coupled
with LSD1 and CRISPR/dCas9 domain with LSD1, G9a and SUV39h1. These
plasmids are programmed to target the IE enhancer element in the
IL4 locus. LSD1 is a demethylase that removes positive histone
marks by demethylating H3K4me1/2. G9a and SUV39h1 are histone
methyltransferases that deposit the repressive histone marks,
H3K9me1/2/3. The plasmid constructs were delivered into D10G4.1
cells (a mouse Th2 cell line) using either electroporation or viral
transduction and were then sorted based on GFP
expression.Results:Upon successfully transfecting the TALE-LSD1
plasmid into D10G4.1 cells, we observe that the cells express the
protein through western blot. Upon activation of the cells using
PMA/Ionomycin, we expected to observe the decrease of IL4
expression. However, we did not see any significant decrease in IL4
expression. Hence, we considered cloning our enzymes into a
CRISPR/dCas9 system and use a guide RNA to target the same IE
enhancer at IL4 locus. We are currently in the process of
optimizing the delivery of these plasmids into D10G4.1
cells.Conclusions:Our preliminary studies show that the TALE domain
successfully fused to the enzyme, LSD1. We also showed that the
protein is transcribed. However, the construct was not successful
in modifying the expression of IL4 as we expected. We are further
investigating possible alternatives to deliver LSD1 and other
enzymes into cells to optimize efficiency and to see if there is a
causal relationship between the presence of histone marks and gene
expression.
Advisors/Committee Members: Katz, Jonathan (Committee Chair).
Subjects/Keywords: Immunology; epigenetic reprogramming; Th2 cells; T cells
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APA (6th Edition):
Rao Venkata, L. P. (2018). Epigenetic Reprogramming at the Th2 Locus. (Masters Thesis). University of Cincinnati. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=ucin1543838686940608
Chicago Manual of Style (16th Edition):
Rao Venkata, Lakshmi Prakruthi. “Epigenetic Reprogramming at the Th2 Locus.” 2018. Masters Thesis, University of Cincinnati. Accessed August 22, 2019.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1543838686940608.
MLA Handbook (7th Edition):
Rao Venkata, Lakshmi Prakruthi. “Epigenetic Reprogramming at the Th2 Locus.” 2018. Web. 22 Aug 2019.
Vancouver:
Rao Venkata LP. Epigenetic Reprogramming at the Th2 Locus. [Internet] [Masters thesis]. University of Cincinnati; 2018. [cited 2019 Aug 22].
Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1543838686940608.
Council of Science Editors:
Rao Venkata LP. Epigenetic Reprogramming at the Th2 Locus. [Masters Thesis]. University of Cincinnati; 2018. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1543838686940608
University of Edinburgh
19.
Ruetz, Tyson Joel.
Smad2/3 potentiate cell identity conversions with master transcription factors.
Degree: PhD, 2016, University of Edinburgh
URL: http://hdl.handle.net/1842/21703
► The exogenous expression of master transcription factors (TFs) to drive cell identity changes is an exciting and powerful approach to cell and tissue engineering. Yet,…
(more)
▼ The exogenous expression of master transcription factors (TFs) to drive cell identity changes is an exciting and powerful approach to cell and tissue engineering. Yet, the generation of desired cell types is often plagued by inefficiency and inability to produce mature cell types. Through investigations of the molecular mechanisms of induced pluripotent stem cell (iPSC) generation, I discovered that expression of constitutively active Smad2/3 (Smad2CA/3CA), together with the Yamanaka factors, could dramatically improve the efficiency of reprogramming. Mechanistically, SMAD3 interacted with both co-activators and reprogramming factors, bridging their interaction during reprogramming. Because SMAD2/3 interact with a multitude of master TFs in different cell types, I tested the conversions of B cells to macrophages, myoblasts to adipocytes, and human fibroblasts to neurons. Remarkably, each conversion system was markedly enhanced when the master TFs were co-expressed with Smad3CA. These results revealed the existence of shared molecular mechanisms underlying diverse TF-mediated cellular conversions, and demonstrated SMAD2/3 as a widely applicable cofactor that potentiates the generation of diverse cell types with profound efficiency and maturity.
Subjects/Keywords: 572.8; TGF-ß; reprogramming; stem cell
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APA (6th Edition):
Ruetz, T. J. (2016). Smad2/3 potentiate cell identity conversions with master transcription factors. (Doctoral Dissertation). University of Edinburgh. Retrieved from http://hdl.handle.net/1842/21703
Chicago Manual of Style (16th Edition):
Ruetz, Tyson Joel. “Smad2/3 potentiate cell identity conversions with master transcription factors.” 2016. Doctoral Dissertation, University of Edinburgh. Accessed August 22, 2019.
http://hdl.handle.net/1842/21703.
MLA Handbook (7th Edition):
Ruetz, Tyson Joel. “Smad2/3 potentiate cell identity conversions with master transcription factors.” 2016. Web. 22 Aug 2019.
Vancouver:
Ruetz TJ. Smad2/3 potentiate cell identity conversions with master transcription factors. [Internet] [Doctoral dissertation]. University of Edinburgh; 2016. [cited 2019 Aug 22].
Available from: http://hdl.handle.net/1842/21703.
Council of Science Editors:
Ruetz TJ. Smad2/3 potentiate cell identity conversions with master transcription factors. [Doctoral Dissertation]. University of Edinburgh; 2016. Available from: http://hdl.handle.net/1842/21703
University of Toronto
20.
Jayakumaran, Gowtham.
Molecular Mechanisms Regulating Somatic Reprogramming.
Degree: 2014, University of Toronto
URL: http://hdl.handle.net/1807/67955
► In reprogramming, cellular transition to pluripotency only occurs in few cells. My thesisis focused on exploring the mechanisms underlying the successful transition of somatic cells…
(more)
▼ In reprogramming, cellular transition to pluripotency only occurs in few cells. My thesisis focused on exploring the mechanisms underlying the successful transition of somatic cells to pluripotent stem cells. Our lab has previously reported reprogramming as a multistep process characterized by initiation, maturation, and stabilization phases based on temporal changes in gene expression. The stabilization phase marks the successful acquisition of pluripotency. Using a functional RNAi screen targeting genes specificallyenriched in cells poised to become pluripotent, I show that distinct molecular networks control the acquisition and subsequent maintenance of pluripotency. Furthermore, I also reveal the functional role of a new class of RNAs, called long intergenic noncoding RNAs (lincRNAs), in the mesenchymal-to-epithelial transition during the initiation phase. Next, I present a novel mouse piggybac primary reprogramming system that ismore robust and efficient than the conventional mouse secondary reprogramming systems and illustrate its utility for mechanistic studies.
M.Sc.
Advisors/Committee Members: Wrana, L Jeffrey, Molecular and Medical Genetics.
Subjects/Keywords: Cell plasticity; NGS; Reprogramming; Stem cells; 0307
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APA (6th Edition):
Jayakumaran, G. (2014). Molecular Mechanisms Regulating Somatic Reprogramming. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/67955
Chicago Manual of Style (16th Edition):
Jayakumaran, Gowtham. “Molecular Mechanisms Regulating Somatic Reprogramming.” 2014. Masters Thesis, University of Toronto. Accessed August 22, 2019.
http://hdl.handle.net/1807/67955.
MLA Handbook (7th Edition):
Jayakumaran, Gowtham. “Molecular Mechanisms Regulating Somatic Reprogramming.” 2014. Web. 22 Aug 2019.
Vancouver:
Jayakumaran G. Molecular Mechanisms Regulating Somatic Reprogramming. [Internet] [Masters thesis]. University of Toronto; 2014. [cited 2019 Aug 22].
Available from: http://hdl.handle.net/1807/67955.
Council of Science Editors:
Jayakumaran G. Molecular Mechanisms Regulating Somatic Reprogramming. [Masters Thesis]. University of Toronto; 2014. Available from: http://hdl.handle.net/1807/67955
University of Toronto
21.
DiLabio, Julia Alexandra Maria.
Reprogramming Mouse Glioma Stem Cells with Defined Factors.
Degree: 2012, University of Toronto
URL: http://hdl.handle.net/1807/42904
► This thesis shows that p53-deficient mouse glioma brain tumour stem cells (BTSCs), which fail to express pluripotency factors, can be reprogrammed with specific transcription factors…
(more)
▼ This thesis shows that p53-deficient mouse glioma brain tumour stem cells (BTSCs), which fail to express pluripotency factors, can be reprogrammed with specific transcription factors to generate iPS cell lines (GNS-iPS) expressing endogenous pluripotency factors (Nanog, Oct4, and Rex1). GNS-iPS cell lines formed embryoid bodies (EBs) in vitro and undifferentiated growths in vivo that phenotypically did not resemble tumours derived from non-reprogrammed BTSCs. EBs formed from one GNS-iPS cell line expressed markers of mesoderm, endoderm, and ectoderm. Tumours produced from GNS-iPS cells had reduced astrocytic marker (GFAP) expression compared to those generated from control iPS cell lines or non-reprogrammed BTSCs. Preliminary results suggest that the reprogrammed cells can be re-differentiated into cells that show neural precursor phenotype. These findings suggest that BTSCs can acquire aspects of the pluripotent state with a defined set of transcription factors, opening the door for further exploration of reprogramming strategies to attenuate the cancer phenotype.
MAST
Advisors/Committee Members: Dirks, Peter Benjamin, Laboratory Medicine and Pathobiology.
Subjects/Keywords: cancer; glioma; reprogramming; stem cells; iPS; 0307
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APA (6th Edition):
DiLabio, J. A. M. (2012). Reprogramming Mouse Glioma Stem Cells with Defined Factors. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/42904
Chicago Manual of Style (16th Edition):
DiLabio, Julia Alexandra Maria. “Reprogramming Mouse Glioma Stem Cells with Defined Factors.” 2012. Masters Thesis, University of Toronto. Accessed August 22, 2019.
http://hdl.handle.net/1807/42904.
MLA Handbook (7th Edition):
DiLabio, Julia Alexandra Maria. “Reprogramming Mouse Glioma Stem Cells with Defined Factors.” 2012. Web. 22 Aug 2019.
Vancouver:
DiLabio JAM. Reprogramming Mouse Glioma Stem Cells with Defined Factors. [Internet] [Masters thesis]. University of Toronto; 2012. [cited 2019 Aug 22].
Available from: http://hdl.handle.net/1807/42904.
Council of Science Editors:
DiLabio JAM. Reprogramming Mouse Glioma Stem Cells with Defined Factors. [Masters Thesis]. University of Toronto; 2012. Available from: http://hdl.handle.net/1807/42904
University of New South Wales
22.
Artuz, Crisbel Marie.
DNA binding proteins and cell fate.
Degree: Biotechnology & Biomolecular Sciences, 2015, University of New South Wales
URL: http://handle.unsw.edu.au/1959.4/54400
;
https://unsworks.unsw.edu.au/fapi/datastream/unsworks:34914/SOURCE02?view=true
► Sequence-specific DNA binding proteins, known as transcription factors, play a central role in the control of eukaryotic gene regulation. Understanding the mechanisms through which DNA…
(more)
▼ Sequence-specific DNA binding proteins, known as transcription factors, play a central role in the control of eukaryotic gene regulation. Understanding the mechanisms through which DNA binding domains recognise their target sequences will greatly improve our understanding of genetic diseases that result from mutations in DNA binding domains and gene promoters. Such information will also assist in the design of factors capable of artificially controlling gene expression. The zinc finger motif, commonly present in tandem arrays of three or more fingers, is the most prevalent DNA recognition structure found in eukaryotic transcription factors. The first project in this thesis aimed to better understand how zinc finger domains bind DNA by examining the two-zinc finger motif of the transcriptional regulator and oncogene ZNF217. By performing a comprehensive mutagenesis analysis, we were able to identify the amino acid residues that are essential for DNA recognition. Our findings indicate that ZNF217 binds to its preferred consensus site by a novel mechanism, an understanding of which may lead to a better appreciation of diseases that result from dysregulation of ZNF217 oncogenic function, and ultimately to the design of novel therapeutic strategies. In the second project, we examined the potential of DNA binding proteins to alter gene expression networks and hence cell fate, in the context of
reprogramming fibroblasts towards the megakaryocytic lineage. Megakaryocytes are required for the production of platelets, which are essential for blood coagulation. Reduction in their numbers causes a life-threatening condition termed thrombocytopenia, which is currently treated by platelet transfusions. However, this treatment is restricted by the short storage life and limited supply of platelet concentrates. To investigate alternative approaches, we examined the potential of ectopic expression of combinations of transcription factors to direct fibroblasts towards the megakaryocyte lineage. We have discovered that over-expression of a combination of GATA1 or its mutant isoform, GATA1 short (GATA1s), FLI1 and TAL1 can drive phenotypic changes consistent with partial
reprogramming of fibroblasts towards the megakaryocyte lineage, laying the foundation for follow up studies.
Advisors/Committee Members: Crossley, Merlin, Biotechnology & Biomolecular Sciences, Faculty of Science, UNSW.
Subjects/Keywords: Megakaryopoiesis; ZNF217; DNA binding; Reprogramming; Transdifferentiation
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APA (6th Edition):
Artuz, C. M. (2015). DNA binding proteins and cell fate. (Doctoral Dissertation). University of New South Wales. Retrieved from http://handle.unsw.edu.au/1959.4/54400 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:34914/SOURCE02?view=true
Chicago Manual of Style (16th Edition):
Artuz, Crisbel Marie. “DNA binding proteins and cell fate.” 2015. Doctoral Dissertation, University of New South Wales. Accessed August 22, 2019.
http://handle.unsw.edu.au/1959.4/54400 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:34914/SOURCE02?view=true.
MLA Handbook (7th Edition):
Artuz, Crisbel Marie. “DNA binding proteins and cell fate.” 2015. Web. 22 Aug 2019.
Vancouver:
Artuz CM. DNA binding proteins and cell fate. [Internet] [Doctoral dissertation]. University of New South Wales; 2015. [cited 2019 Aug 22].
Available from: http://handle.unsw.edu.au/1959.4/54400 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:34914/SOURCE02?view=true.
Council of Science Editors:
Artuz CM. DNA binding proteins and cell fate. [Doctoral Dissertation]. University of New South Wales; 2015. Available from: http://handle.unsw.edu.au/1959.4/54400 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:34914/SOURCE02?view=true
University of Minnesota
23.
Yang, Ying.
Reprogramming of hepatic progenitor cells towards a beta-cell character using Pdx1, Ngn3 and MafA.
Degree: MS, Stem cell biology, 2012, University of Minnesota
URL: http://purl.umn.edu/160346
► The pancreas and liver arises from adjacent areas in the anterior endoderm of the developing embryo. This close relatedness underlies the possibility of direct reprogramming…
(more)
▼ The pancreas and liver arises from adjacent areas in the anterior endoderm of the developing embryo. This close relatedness underlies the possibility of direct reprogramming of the liver cells or hepatocytes towards pancreatic beta cells.
In the present study we show that hepatoblasts in undissociated early-stage liver buds can be reprogrammed towards a beta cell-like cell fate by ectopic expression of the pancreatic transcription genes (Pdx1, Ngn3, and MafA) using a polycistronic adenovirus. The reprogramming happens by 3 days after Ad-PNM transduction. Dissociated hepatoblasts isolated from different developmental stages of embryonic livers, which are considered as hepatic progenitor cells, also could be reprogrammed efficiently by Ad-PNM. This was associated with approximately 20% (E18) to 70% (E11) of hepatoblasts expressing insulin and C-Peptide along with a significant increase in endocrine gene profiles and down-regulation of liver markers. Moreover the reprogrammed cells were seen to express GFP when hepatoblasts were isolated from Pdx1-GFP transgenic mice, indicating transcription of the endogenous Pdx1, a hallmark for genuine reprogramming. This allowed us to sort the green fluorescent cells which, upon stimulating with low (2.8mM) or high (20mM) glucose, failed to show significant glucose-sensitive insulin release. However, these cells could maintain the blood glucose levels of diabetic mice at a stable and normal level for one month after transplantation.
In summary, hepatic progenitor cells, which may possess a similar epigenetic pattern to pancreatic progenitor cells, can be reprogrammed by overexpressing pancreatic transcription factors. This may be a promising resource of cell therapy for diabetes.
Subjects/Keywords: Beta cells; Cell reprogramming; Hepatic progenitor cells
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APA (6th Edition):
Yang, Y. (2012). Reprogramming of hepatic progenitor cells towards a beta-cell character using Pdx1, Ngn3 and MafA. (Masters Thesis). University of Minnesota. Retrieved from http://purl.umn.edu/160346
Chicago Manual of Style (16th Edition):
Yang, Ying. “Reprogramming of hepatic progenitor cells towards a beta-cell character using Pdx1, Ngn3 and MafA.” 2012. Masters Thesis, University of Minnesota. Accessed August 22, 2019.
http://purl.umn.edu/160346.
MLA Handbook (7th Edition):
Yang, Ying. “Reprogramming of hepatic progenitor cells towards a beta-cell character using Pdx1, Ngn3 and MafA.” 2012. Web. 22 Aug 2019.
Vancouver:
Yang Y. Reprogramming of hepatic progenitor cells towards a beta-cell character using Pdx1, Ngn3 and MafA. [Internet] [Masters thesis]. University of Minnesota; 2012. [cited 2019 Aug 22].
Available from: http://purl.umn.edu/160346.
Council of Science Editors:
Yang Y. Reprogramming of hepatic progenitor cells towards a beta-cell character using Pdx1, Ngn3 and MafA. [Masters Thesis]. University of Minnesota; 2012. Available from: http://purl.umn.edu/160346
University of New South Wales
24.
Liu, Menghan.
Metabolic reprogramming associated with the epithelial-mesenchymal transition in pancreatic cancer.
Degree: Medical Sciences, 2017, University of New South Wales
URL: http://handle.unsw.edu.au/1959.4/58654
;
https://unsworks.unsw.edu.au/fapi/datastream/unsworks:46542/SOURCE02?view=true
► The high rate of mortality associated with pancreatic cancer is largely attributable to its tendency for metastatic spread and resistance to chemotherapies, both of which…
(more)
▼ The high rate of mortality associated with pancreatic cancer is largely attributable to its tendency for metastatic spread and resistance to chemotherapies, both of which partially underlined by the epithelial-mesenchymal transition (EMT). While the role of Warburg metabolism has been recognised in supporting rapid cellular growth and proliferation in many cancer types, less is known about the metabolic changes occurring during EMT, particularly in the context of pancreatic cancer. The aim of this thesis was to induce EMT via exposure to two physiologically relevant EMT inducers, Tumour Necrosis Factor (TNF) and Transformation Growth Factor (TGF), and through stably overexpressing Snail in pancreatic cancer and non-tumourigenic human pancreatic ductal epithelial (HPDE) cells to examine the metabolic consequences. Inductions of EMT by TNF and TGF in Panc-1 as well as Snail overexpression in Panc-1 and HPDE were uniformly associated with augmentations of glucose uptake and lactate secretion, despite differential molecular changes. No effect on oxidative metabolism was seen with TNF or TGF treatment but Panc-1 and HPDE cells overexpressing Snail displayed reductions in mitochondrial electron transport chain complexes and, in the case of Panc-1, downregulated oxygen consumption. Various changes were also observed concerning lipid synthesis and glutamine oxidation in the EMT models. Attempts to reverse the EMT-associated metabolic
reprogramming in Panc-1 cells via pharmacological means had minimal impact on the overall EMT status. Collectively, these findings suggest that major metabolic alterations take place during EMT in pancreatic cancer, likely involving the enhancement of aerobic glycolysis. Further research into the underlying mechanisms is required for designing metabolic strategies to help eliminate EMT cells or reverse the EMT process in pancreatic cancer.
Advisors/Committee Members: Turner, Nigel, Medical Sciences, Faculty of Medicine, UNSW, Saunders, Darren, Medical Sciences, Faculty of Medicine, UNSW.
Subjects/Keywords: epithelial-mescenchymal transition; Metabolic reprogramming; Pancreatic cancer
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APA (6th Edition):
Liu, M. (2017). Metabolic reprogramming associated with the epithelial-mesenchymal transition in pancreatic cancer. (Doctoral Dissertation). University of New South Wales. Retrieved from http://handle.unsw.edu.au/1959.4/58654 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:46542/SOURCE02?view=true
Chicago Manual of Style (16th Edition):
Liu, Menghan. “Metabolic reprogramming associated with the epithelial-mesenchymal transition in pancreatic cancer.” 2017. Doctoral Dissertation, University of New South Wales. Accessed August 22, 2019.
http://handle.unsw.edu.au/1959.4/58654 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:46542/SOURCE02?view=true.
MLA Handbook (7th Edition):
Liu, Menghan. “Metabolic reprogramming associated with the epithelial-mesenchymal transition in pancreatic cancer.” 2017. Web. 22 Aug 2019.
Vancouver:
Liu M. Metabolic reprogramming associated with the epithelial-mesenchymal transition in pancreatic cancer. [Internet] [Doctoral dissertation]. University of New South Wales; 2017. [cited 2019 Aug 22].
Available from: http://handle.unsw.edu.au/1959.4/58654 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:46542/SOURCE02?view=true.
Council of Science Editors:
Liu M. Metabolic reprogramming associated with the epithelial-mesenchymal transition in pancreatic cancer. [Doctoral Dissertation]. University of New South Wales; 2017. Available from: http://handle.unsw.edu.au/1959.4/58654 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:46542/SOURCE02?view=true
University of New South Wales
25.
Han, Jinnuo.
Reprogramming of human somatic cells using epigenetic and non-genetic methods.
Degree: Psychiatry, 2010, University of New South Wales
URL: http://handle.unsw.edu.au/1959.4/45452
;
https://unsworks.unsw.edu.au/fapi/datastream/unsworks:8747/SOURCE02?view=true
► Chemicals that regulate cell epigenetic states by inhibiting DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) have been used to improve somatic cell reprogramming during somatic…
(more)
▼ Chemicals that regulate cell epigenetic states by inhibiting DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) have been used to improve somatic cell
reprogramming during somatic cell nuclear transfer (SCNT) and induced pluripotent stem cell (iPSC) generation. However,
reprogramming induced by fusion with embryonic stem cells (ESCs) and by exposure to pluripotent cell extracts has not been well studied, especially in human cells.Data presented in this thesis first optimized hESC-somatic cell fusion condition by applying three conventional fusion methods and the results provide direct evidence that hESCs have the ability to reprogram human somatic cells. Using a combination of immunoblotting and immunocytochemistry, I also demonstrated that hESC extracts can reprogram human somatic cells towards pluripotency.
Reprogramming was confirmed by morphological changes and quantitative PCR (qPCR) analysis on pluripotency related genes. When somatic cells were pre-treated with DNMT and HDAC inhibitors before exposing to hESC extracts, changes in global epigenetic states were observed and morphological analysis revealed a higher rate of hESC-like colony formation than without pre-treatment. qPCR demonstrated that pluripotency genes were upregulated to higher levels as compared to those of somatic cells treated with hESC extracts alone. Thus, pre-modifying the epigenetics of somatic cells could be used to improve the efficiency of
reprogramming process. These reprogrammed cells could not be maintained for a long time due to the up-regulation of apoptotic genes in the culture conditions used here. However, under directed differentiation conditions, the reprogrammed cells exhibited differentiation ability into neuronal cells suggesting that, although complete
reprogramming was not achieved, the cells could be transdifferentiated after partial
reprogramming.In summary, this study showed that both hESC-somatic cell fusion and hESC extracts could induce partial
reprogramming of human somatic cells. The latter was improved by pre-treating of the somatic cells with epigenetic modifying agents. The resulting reprogrammed cells could be differentiated into neuronal cells. Thus, the combination of epigenetic and hESC extract treatment for inducing human somatic cell
reprogramming provides a new way for in vitro
reprogramming and generating patient-specific cell lines.
Advisors/Committee Members: Sidhu, Kuldip, Psychiatry, Faculty of Medicine, UNSW, Pimanda, John, Clinical School - Prince of Wales Hospital, Faculty of Medicine, UNSW.
Subjects/Keywords: cell fusion; Cell extract; Reprogramming; Epigenetics
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APA (6th Edition):
Han, J. (2010). Reprogramming of human somatic cells using epigenetic and non-genetic methods. (Doctoral Dissertation). University of New South Wales. Retrieved from http://handle.unsw.edu.au/1959.4/45452 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:8747/SOURCE02?view=true
Chicago Manual of Style (16th Edition):
Han, Jinnuo. “Reprogramming of human somatic cells using epigenetic and non-genetic methods.” 2010. Doctoral Dissertation, University of New South Wales. Accessed August 22, 2019.
http://handle.unsw.edu.au/1959.4/45452 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:8747/SOURCE02?view=true.
MLA Handbook (7th Edition):
Han, Jinnuo. “Reprogramming of human somatic cells using epigenetic and non-genetic methods.” 2010. Web. 22 Aug 2019.
Vancouver:
Han J. Reprogramming of human somatic cells using epigenetic and non-genetic methods. [Internet] [Doctoral dissertation]. University of New South Wales; 2010. [cited 2019 Aug 22].
Available from: http://handle.unsw.edu.au/1959.4/45452 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:8747/SOURCE02?view=true.
Council of Science Editors:
Han J. Reprogramming of human somatic cells using epigenetic and non-genetic methods. [Doctoral Dissertation]. University of New South Wales; 2010. Available from: http://handle.unsw.edu.au/1959.4/45452 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:8747/SOURCE02?view=true
University of New South Wales
26.
Yeola, Avani.
Generating multipotent stem cells from primary human adipocytes for tissue repair.
Degree: Prince of Wales Clinical School, 2018, University of New South Wales
URL: http://handle.unsw.edu.au/1959.4/60268
► Current trends in regenerative medicine for tissue repair focus on generating tissue-specific stem cells. However, given the complexity of most tissues, the ideal stem cell…
(more)
▼ Current trends in regenerative medicine for tissue repair focus on generating tissue-specific stem cells. However, given the complexity of most tissues, the ideal stem cell would be one that could undergo multilineage context-dependent differentiation to bring about holistic repair of the injured tissue. This thesis describes application of a vector- and transcription factor-free method to reprogram human somatic cells into induced Multipotent Stem (iMS) cells utilizing the combination of 5-Azacytidine and recombinant human Platelet Derived Growth Factor-AB. I optimized xenofree conditions for this Demethylation Cytokine-induced (DCi) reprogramming technique that yielded autologous iMS cells at high efficiency from human adipocytes harvested from subjects aged 18-80 years. Human iMS cells display in vitro colony forming and serial re-plating ability, multilineage differentiation capacity and maintain a stable karyotype over several months. They express MSC markers but not markers of the blood lineage. iMS cells can be expanded long-term in medium containing autologous/allogeneic human serum. They have a transcriptional profile distinct to adipocytes or tissue-derived mesenchymal stem cells. IPA analysis revealed activation of genes associated with embryonic stem cells, EMT, PDGF signaling and downstream JAK/STAT, PI3K/AKT/mTOR pathways in iMS cells compared to adipocytes. Although iMS cells expressed pluripotency factors (OCT4, Nanog, SOX2 and SSEA4) they lacked spontaneous teratogenicity characteristic of pluripotent cells. When transplanted into injured intervertebral disc of NOD/SCID mice, human iMS cells were retained at transplant site for the duration of assessment (1 year) with no evidence of malignant transformation. iMS cells displayed in vivo plasticity and directly contributed to formation of new blood vessels, bone, cartilage and smooth muscle at the site of injury. To assess the specificity of cell plasticity, human iMS cells were also injected into cardiotoxin injured tibialis anterior muscle of SCID/beige mice. Donor iMS cells contributed to hCD56 expressing muscle satellite cells and hSpectrin expressing myofibres without heterotopic transformation or aberrant differentiation. Together these findings demonstrate the feasibility and utility of DCi reprogramming for generation of safe, therapeutically relevant autologous iMS cells, and provide a solid foundation to evaluate their tissue regenerative potential in controlled clinical trials.
Subjects/Keywords: Multipotent stem cells; Regenerative medicine; Cell reprogramming
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APA (6th Edition):
Yeola, A. (2018). Generating multipotent stem cells from primary human adipocytes for tissue repair. (Doctoral Dissertation). University of New South Wales. Retrieved from http://handle.unsw.edu.au/1959.4/60268
Chicago Manual of Style (16th Edition):
Yeola, Avani. “Generating multipotent stem cells from primary human adipocytes for tissue repair.” 2018. Doctoral Dissertation, University of New South Wales. Accessed August 22, 2019.
http://handle.unsw.edu.au/1959.4/60268.
MLA Handbook (7th Edition):
Yeola, Avani. “Generating multipotent stem cells from primary human adipocytes for tissue repair.” 2018. Web. 22 Aug 2019.
Vancouver:
Yeola A. Generating multipotent stem cells from primary human adipocytes for tissue repair. [Internet] [Doctoral dissertation]. University of New South Wales; 2018. [cited 2019 Aug 22].
Available from: http://handle.unsw.edu.au/1959.4/60268.
Council of Science Editors:
Yeola A. Generating multipotent stem cells from primary human adipocytes for tissue repair. [Doctoral Dissertation]. University of New South Wales; 2018. Available from: http://handle.unsw.edu.au/1959.4/60268
Utah State University
27.
Moley, Laura A.
Epigenetic Reprogramming, Apoptosis, and Developmental Competence in Cloned Embryos.
Degree: PhD, Animal, Dairy, and Veterinary Sciences, 2019, Utah State University
URL: https://digitalcommons.usu.edu/etd/7571
► Cloning through somatic cell nuclear transfer (SCNT) remains highly inefficient twenty years after the first demonstration of the technology with the birth of Dolly.…
(more)
▼ Cloning through somatic cell nuclear transfer (SCNT) remains highly inefficient twenty years after the first demonstration of the technology with the birth of Dolly. By increasing efficiency by selecting the embryos early in development that are most likely to succeed following transfer into a surrogate mother, the technology could be more routinely utilized to enhance animal agriculture production. SCNT is believed to be highly inefficient as a result of incorrect DNA methylation and gene expression that are accumulated because of the SCNT technique. We proposed the use of a non-toxic, non-invasive detector of cell death, to quantitatively assess embryo competency prior to embryo transfer. We believed we could use SR-FLICA to identify the embryos with low levels of cell death as a result of proper DNA methylation and gene expression. By analyzing the whole embryo, differences in gene expression and DNA methylation were identified in embryos with high and low levels of cell death. However, the level of cell death did not prove to be a reliable indicator of embryo quality in predicting pregnancy outcome. This data supports the commonly held hypothesis that DNA methylation and gene expression after SCNT have random defects as a result of the random nature of resetting the DNA for embryo development. More research is required to identify the embryos which will prove to be successful following SCNT and embryo transfer.
Advisors/Committee Members: S. Clay Isom, Abby D. Benninghoff, John Stevens, ;.
Subjects/Keywords: genetic; epigenetic; apoptosis; reprogramming; Animal Sciences
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APA (6th Edition):
Moley, L. A. (2019). Epigenetic Reprogramming, Apoptosis, and Developmental Competence in Cloned Embryos. (Doctoral Dissertation). Utah State University. Retrieved from https://digitalcommons.usu.edu/etd/7571
Chicago Manual of Style (16th Edition):
Moley, Laura A. “Epigenetic Reprogramming, Apoptosis, and Developmental Competence in Cloned Embryos.” 2019. Doctoral Dissertation, Utah State University. Accessed August 22, 2019.
https://digitalcommons.usu.edu/etd/7571.
MLA Handbook (7th Edition):
Moley, Laura A. “Epigenetic Reprogramming, Apoptosis, and Developmental Competence in Cloned Embryos.” 2019. Web. 22 Aug 2019.
Vancouver:
Moley LA. Epigenetic Reprogramming, Apoptosis, and Developmental Competence in Cloned Embryos. [Internet] [Doctoral dissertation]. Utah State University; 2019. [cited 2019 Aug 22].
Available from: https://digitalcommons.usu.edu/etd/7571.
Council of Science Editors:
Moley LA. Epigenetic Reprogramming, Apoptosis, and Developmental Competence in Cloned Embryos. [Doctoral Dissertation]. Utah State University; 2019. Available from: https://digitalcommons.usu.edu/etd/7571
Case Western Reserve University
28.
Lager, Angela Marie.
Cell Reprogramming Technologies for Treatment and
Understanding of Genetic Disorders of Myelin.
Degree: PhD, Genetics, 2015, Case Western Reserve University
URL: http://rave.ohiolink.edu/etdc/view?acc_num=case1427898199
► The oligodendrocyte lineage is essential for high-fidelity information transfer in neural circuits of the central nervous system. Oligodendrocytes arise from a pool of migratory progenitor…
(more)
▼ The oligodendrocyte lineage is essential for
high-fidelity information transfer in neural circuits of the
central nervous system. Oligodendrocytes arise from a pool of
migratory progenitor cells that populate the brain and spinal cord
shortly before birth. These oligodendrocyte progenitor cells
undergo subsequent differentiation into mature oligodendrocytes, a
cell whose primary function is to generate a multilayer
protein-lipid membrane around axons termed myelin. Myelin segments
allow saltatory conduction of action potentials down the axon,
increasing impulse velocity by as much as 100-fold. Therefore,
oligodendrocytes are thought to contribute to efficient signal
processing in local microcircuits and are required for
long-distance propagation of action potentials by projection
neurons.The importance of oligodendrocytes in central nervous
system function is underscored by the prevalence of neurological
diseases characterized by abnormal myelination. These diseases,
collectively termed leukodystrophies, encompass a spectrum of
disorders associated with mutations in over 40 different
oligodendrocyte lineage-specific genes. Although the genetic
etiology for a majority of these disorders is well understood, less
is known about how genetic abnormalities underlie cellular
dysfunction and overt disease pathology. As there are currently no
standard treatments for patients suffering from leukodystrophies,
addressing this gap is of fundamental importance.Recent use of
mouse genetic models and cell
reprogramming technologies has
dramatically improved our ability to understand how genetic
mutations underlie disease at the molecular, cellular, and systems
level. We sought to adapt these technologies to develop a method
for obtaining oligodendrocyte progenitor cells—a previously
inaccessible cell type. Herein, I describe our identification of
oligodendrocyte lineage-specific transcription factors and their
subsequent use in direct
reprogramming of mouse fibroblasts to
induced oligodendrocyte progenitor cells (iOPCs). iOPCs exhibit
morphology and gene expression profiles similar to bona fide
oligodendrocyte progenitors, can be expanded in vitro in a
progenitor state capable of differentiating into mature
multiprocessed oligodendrocytes, and form compact myelin when
grafted into the mouse central nervous system. We have also
developed a second method that allows us to direct the
differentiation of oligodendrocyte progenitor cells from wild type
and mutant mouse pluripotent stem cell populations. By
systematically treating mouse pluripotent stem cells with small
molecules and growth factors that mimic growth factor conditions
observed during development, we developed a robust and rapid method
for obtaining a pure population of oligodendrocyte progenitor
cells. Thus, through these methods, we gain new experimental access
to oligodendrocyte lineage cells for the first time.With the
development of new protocols for obtaining pure populations of
oligodendrocyte progenitor cells and mature oligodendrocytes, we
can begin to address gaps…
Advisors/Committee Members: Tesar, Paul (Advisor), Conlon, Ronald (Committee Chair).
Subjects/Keywords: Developmental Biology; Genetics; myelin; oligodendrocytes; cell reprogramming; regenerative therapy; direct reprogramming; myelin repair
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APA ·
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MLA ·
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APA (6th Edition):
Lager, A. M. (2015). Cell Reprogramming Technologies for Treatment and
Understanding of Genetic Disorders of Myelin. (Doctoral Dissertation). Case Western Reserve University. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=case1427898199
Chicago Manual of Style (16th Edition):
Lager, Angela Marie. “Cell Reprogramming Technologies for Treatment and
Understanding of Genetic Disorders of Myelin.” 2015. Doctoral Dissertation, Case Western Reserve University. Accessed August 22, 2019.
http://rave.ohiolink.edu/etdc/view?acc_num=case1427898199.
MLA Handbook (7th Edition):
Lager, Angela Marie. “Cell Reprogramming Technologies for Treatment and
Understanding of Genetic Disorders of Myelin.” 2015. Web. 22 Aug 2019.
Vancouver:
Lager AM. Cell Reprogramming Technologies for Treatment and
Understanding of Genetic Disorders of Myelin. [Internet] [Doctoral dissertation]. Case Western Reserve University; 2015. [cited 2019 Aug 22].
Available from: http://rave.ohiolink.edu/etdc/view?acc_num=case1427898199.
Council of Science Editors:
Lager AM. Cell Reprogramming Technologies for Treatment and
Understanding of Genetic Disorders of Myelin. [Doctoral Dissertation]. Case Western Reserve University; 2015. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=case1427898199
University of Helsinki
29.
Pörsti, Elina.
CRISPR activator-mediated reprogramming of human neuroectodermal stem cells to iPS cells.
Degree: Medicinska fakulteten, 2018, University of Helsinki
URL: http://hdl.handle.net/10138/236384
► The capability to generate human induced pluripotent stem cells (iPSC) from somatic cells provides remarkable possibilities for regenerative medicine. However, prior to clinical applications the…
(more)
▼ The capability to generate human induced pluripotent stem cells (iPSC) from somatic cells provides remarkable possibilities for regenerative medicine. However, prior to clinical applications the process of reprogramming should be optimized and carefully characterized.
The purpose of this study was to get insight in reprogramming of human somatic cells to pluripotency using CRISPR-dCas9 activator system (CRISPRa). CRISPRa is a RNA guided bacterial nuclease system that has been modified for gene expression control. The study had two subprojects. The aims of the first subproject were 1) to reprogram hNESCs to pluripotency with CRISPRa in 2D culture, 2) to determine the efficacy of reprogramming and 3) to study whether CRISPRa-mediated pluripotent reprogramming pathway involves a mesendoderm-resembling intermediate state. The aim of the second subproject was to explore the possibility of CRISPRa-mediated endogenous gene activation and reprogramming to pluripotency also in 3D cell cultures.
I performed the reprogramming in 2D and 3D cell cultures by using a dCas9 activator to induce different combinations of endogenous pluripotency reprogramming factors OCT4 (octamer-binding transcription factor 4), SOX2 (Sex determining region Y-box 2), NANOG, c-MYC, KLF4 (Krüppel-like factor 4) and LIN28. I analysed the results of the reprogramming at protein level, using alkaline phosphatase staining and immunocytochemistry, and at mRNA level, using qRT-PCR.
The 2D reprogramming served as a proof-of-principle for reprogramming with CRISPRa. This study shows, that CRISPRa can be used to reprogram human neural stem cells to iPSC with different combinations of pluripotency reprogramming factors or by inducing a single master-regulator gene, OCT4. In addition, the reprogramming process was very efficient. I did not detect mesendodermal intermediate state in CRISPRa-mediated reprogramming to pluripotency, in contrast to published results from transgene- and small molecules-based reprogramming studies. Thus, this result suggests that the pathway leading to pluripotency differs between CRISPRa-mediated reprogramming and the two other reprogramming methods. CRISPRa can be used to initiate reprogramming also in 3D cell culture. However, in 3D cell culture the cells were not fully reprogrammed. Based on these findings, I postulate that CRISPRa serves as an alternative method for generating human iPSC. In addition, CRISPRa can be further developed into a platform for direct reprogramming of organoids for in vitro disease modelling in 3D.
Subjects/Keywords: CRISPRa; iPSC; reprogramming; pluripotency; neural stem cell; neurosphere; cerebral organoid; CRISPRa; iPSC; reprogramming; pluripotency; neural stem cell; neurosphere; cerebral organoid
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APA (6th Edition):
Pörsti, E. (2018). CRISPR activator-mediated reprogramming of human neuroectodermal stem cells to iPS cells. (Masters Thesis). University of Helsinki. Retrieved from http://hdl.handle.net/10138/236384
Chicago Manual of Style (16th Edition):
Pörsti, Elina. “CRISPR activator-mediated reprogramming of human neuroectodermal stem cells to iPS cells.” 2018. Masters Thesis, University of Helsinki. Accessed August 22, 2019.
http://hdl.handle.net/10138/236384.
MLA Handbook (7th Edition):
Pörsti, Elina. “CRISPR activator-mediated reprogramming of human neuroectodermal stem cells to iPS cells.” 2018. Web. 22 Aug 2019.
Vancouver:
Pörsti E. CRISPR activator-mediated reprogramming of human neuroectodermal stem cells to iPS cells. [Internet] [Masters thesis]. University of Helsinki; 2018. [cited 2019 Aug 22].
Available from: http://hdl.handle.net/10138/236384.
Council of Science Editors:
Pörsti E. CRISPR activator-mediated reprogramming of human neuroectodermal stem cells to iPS cells. [Masters Thesis]. University of Helsinki; 2018. Available from: http://hdl.handle.net/10138/236384
Universitat Pompeu Fabra
30.
Aulicino, Francesco, 1987-.
Investigating the role of Wnt/β-catenin pathway in pluripotency and somatic cell reprogramming.
Degree: Departament de Ciències Experimentals i de la Salut, 2016, Universitat Pompeu Fabra
URL: http://hdl.handle.net/10803/552942
► La respuesta adaptativa de las células a estímulos externos es un mecanismo fundamental de la existencia de la vida en sí misma. Para este fin,…
(more)
▼ La respuesta adaptativa de las células a estímulos externos es un mecanismo fundamental de la existencia de la vida en sí misma. Para este fin, rutas de señalización y redes de regulación génica evolucionaron elegantemente, traduciendo señales extracelulares en respuestas celulares calibradas con precisión. Entre ellas, la ruta de señalización de Wnt/ß-catenin converge en la regulación de la proteína ß-catenin, que a su vez regula la expresión de genes diana. En particular, la ruta de Wnt/ß-catenin tiene un rol fundamental en el mantenimiento de la pluripotencia y la reprogramación de células somáticas. En esta tesis hemos identificado un papel temporal de actividad de Wnt/ß-catenin durante la reprogramación de células somáticas, lo que controla los niveles de expresión de genes asociados a transición mesenquima-epitelial y senescencia a través de TCF1. Además, la ruta de Wnt/ß-catenin es un regulador clave de la pluripotencia y la auto-renovación de células madre embrionarias de ratón (mESCs). Una pequeña molécula, activadora de la ruta Wnt es usada comúnmente para mantener las células madre embrionarias en “ground state” de pluripotencia. Sin embargo, el rol de la ß-catenin en las mESCs es aún controvertido. Observamos que los modelos disponibles de Knock-Out de ß-catenin producen proteínas truncadas en N-terminal con funciones desconocidas. Por ello, generamos un nuevo Knock-Out usando CRISPR/Cas9, al fin de clarificar funciones de ß-catenina en mESCs.
Hemos encontrado también que el “ground state” de pluripotencia promovido por la activación sostenida de Wnt no puede ser mantenido indefinidamente, resultando esto en un“ lapsed ground state”; debido posiblemente, entre otros factores, a feedback-loop negativos que afectan negativamente la actividad de Wnt/ß-catenin.
Advisors/Committee Members: [email protected] (authoremail), true (authoremailshow), Cosma, Maria Pia, 1970- (director), true (authorsendemail).
Subjects/Keywords: Wnt/ß-catenin; Pluripotency; Reprogramming; ß-catenin; TCF1; Pluripotencia; Reprogramación; 576
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APA (6th Edition):
Aulicino, Francesco, 1. (2016). Investigating the role of Wnt/β-catenin pathway in pluripotency and somatic cell reprogramming. (Thesis). Universitat Pompeu Fabra. Retrieved from http://hdl.handle.net/10803/552942
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Aulicino, Francesco, 1987-. “Investigating the role of Wnt/β-catenin pathway in pluripotency and somatic cell reprogramming.” 2016. Thesis, Universitat Pompeu Fabra. Accessed August 22, 2019.
http://hdl.handle.net/10803/552942.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Aulicino, Francesco, 1987-. “Investigating the role of Wnt/β-catenin pathway in pluripotency and somatic cell reprogramming.” 2016. Web. 22 Aug 2019.
Vancouver:
Aulicino, Francesco 1. Investigating the role of Wnt/β-catenin pathway in pluripotency and somatic cell reprogramming. [Internet] [Thesis]. Universitat Pompeu Fabra; 2016. [cited 2019 Aug 22].
Available from: http://hdl.handle.net/10803/552942.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Aulicino, Francesco 1. Investigating the role of Wnt/β-catenin pathway in pluripotency and somatic cell reprogramming. [Thesis]. Universitat Pompeu Fabra; 2016. Available from: http://hdl.handle.net/10803/552942
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