University of Michigan
Decrypting Intestinal Mucosal Repair.
Degree: PhD, Cellular & Molecular Biology, 2019, University of Michigan
Regeneration is a word that has inspired the imagination of artists and scientists alike ever since the word’s inception in mid-14th century from Latin meaning “being born again.” Today, medical research labs are fascinated with the aim of directing native repair mechanisms to heal damaged tissues.
Amongst the most rapidly renewing tissues in the mammalian body, the lining of the intestine (epithelium) is a particularly pertinent system in which to study regeneration driven by the extraordinary potential of intestinal stem cells (ISC). Prevailing evidence demonstrates the existence of two ISC populations in the intestinal crypts: active stem cells (termed crypt base columnar (CBC) cells), responsible for epithelial cell maintenance during homeostasis, and facultative stem cells (FSC), important to the replenishment of the CBC compartment when damaged (e.g. irradiation, disturbance of the stem cell microenvironment).
In this thesis, I examined the molecular mechanisms regulating the cellular changes mediating the regenerative response stimulated by intestinal damage. The scientific literature describes intestinal regeneration as a complex multiphasic response modulated by a network of signaling factors and cellular compartments (including epithelial Paneth cells and pericryptal subepithelial cells) that aim to restore homeostasis. However, significant knowledge gaps remained with regard
to how the intestine responds to injury, and mobilizes FSC cell populations to remedy the damage.
My studies characterize the intestinal response to irradiation-mediated CBC loss, and propose a mechanism by which damage stimulates the non-epithelial cells in close juxtaposition with the intestinal crypts (termed pericryptal subepithelial cells) to signal to crypt epithelial cells via IGF1 (Chapter II). IGF1 stimulates epithelial cell mTORC1 signaling, which results in mobilization and activation of FSCs to repopulate the vacant CBC compartment.
In my investigations of the intestinal response to irradiation damage, I also demonstrate that commonly employed CreERT2 mouse models exhibit inherent toxicity, with CreERT2 expressing-CBCs exhibiting impaired function (Chapter III). Activation of CreERT2 by tamoxifen treatment leads to DNA damage, which results in delayed intestinal regeneration after irradiation injury. My discoveries inform the GI field in ways to minimize the confounding factor of CreERT2 genotoxicity.
In addition to characterizing the mechanisms directing regeneration from known intestinal injury methods (Chapter II), my studies also characterized a novel method of intestinal damage resulting from acute inhibition of a molecular pathway critical to ISC activity: Notch (Chapter IV). While Notch regulation of the ISC niche has been defined in the context of chronic or persistent Notch modulation, no study has yet sought to understand the consequence of short-term Notch inhibition. My data report rapid Paneth cell loss following acute Notch inhibition, which transiently impairs CBC function, and initiates regeneration of…
Advisors/Committee Members: Samuelson, Linda C (committee member), Fingar, Diane C (committee member), Maillard, Ivan Patrick (committee member), Spence, Jason (committee member).
Subjects/Keywords: regeneration; stem cell; intestine; niche; mouse; organoid; Genetics; Medicine (General); Molecular, Cellular and Developmental Biology; Physiology; Radiology; Science (General); Health Sciences; Science
to Zotero / EndNote / Reference
APA (6th Edition):
Bohin, N. (2019). Decrypting Intestinal Mucosal Repair. (Doctoral Dissertation). University of Michigan. Retrieved from http://hdl.handle.net/2027.42/150044
Chicago Manual of Style (16th Edition):
Bohin, Natacha. “Decrypting Intestinal Mucosal Repair.” 2019. Doctoral Dissertation, University of Michigan. Accessed January 20, 2020.
MLA Handbook (7th Edition):
Bohin, Natacha. “Decrypting Intestinal Mucosal Repair.” 2019. Web. 20 Jan 2020.
Bohin N. Decrypting Intestinal Mucosal Repair. [Internet] [Doctoral dissertation]. University of Michigan; 2019. [cited 2020 Jan 20].
Available from: http://hdl.handle.net/2027.42/150044.
Council of Science Editors:
Bohin N. Decrypting Intestinal Mucosal Repair. [Doctoral Dissertation]. University of Michigan; 2019. Available from: http://hdl.handle.net/2027.42/150044