EXTRINSIC REGULATION OF INTESTINAL STEM CELL PROLIFERATION AND DIFFERENTIATION BY NICHE COMPONENTS

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  • March 21, 2019
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  • Zwarycz, Bailey
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
Abstract
  • The small intestinal epithelium facilitates the absorption of nutrients and provides a barrier against damaging toxins, indigestible contents, and microbes in the intestinal lumen. The epithelium is maintained by a pool of intestinal stem cells (ISCs) that reside at the base of the crypt in a supportive niche environment, made up of both cellular and non-cellular components. Niche cells, including epithelial Paneth cells, subepithelial myofibroblasts, and immune cells, along with the non-cellular extracellular matrix (ECM) provide cues that promote ISC proliferation and differentiation. The niche environment is complex and dynamic, with various cell types present that secrete different growth factors and cytokines in response to intestinal damage, inflammation, and regeneration. Extrinsic niche factors are integral for the survival and proliferation of ISCs; therefore, understanding the influence of individual niche components on ISC behavior is essential for the development of therapeutics for patient health. Here, two components of the ISC niche are investigated for their influence on ISC proliferation and differentiation: cytokines secreted from local immune cells and the underlying ECM scaffold. Through a screen of inflammatory bowel disease-related cytokines, Interleukin 22 demonstrated a concentration-dependent effect on ileal organoid size and survival in vitro. Elevated levels of Interleukin 22 limited ISC expansion in favor of increased progenitor cell differentiation and proliferation, resulting in increased organoids size and expression of antimicrobial gene products. ISC cultures rely on the use of non-intestinal based ECM components for the survival of ISCs in vitro. Using a natural, acellular intestinal scaffold provides a more physiologically relevant substrate for use both in vitro culture systems and for tissue engineering applications. By optimizing decellularization techniques, an acellular porcine small intestinal scaffold was created that retained mucosal architecture, preserved key ECM components, and supported the proliferation and differentiation of mouse small intestinal epithelium. Together, these to findings further the understanding of how extrinsic factors from the niche influence ISCs, which is of particular importance when developing therapies for intestinal disease.
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Advisor
  • Burridge, Keith
  • Otey, Carol
  • Henning, Susan
  • Magness, Scott
  • Major, Michael
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill
Graduation year
  • 2018
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