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Renewal of intestinal stem cells lacking intrinsic survival program requires microbiome and immune signaling input
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Zhang, Xiao. Renewal of intestinal stem cells lacking intrinsic survival program requires microbiome and immune signaling input. Retrieved from https://doi.org/doi:10.7282/t3-003d-wh71

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TitleRenewal of intestinal stem cells lacking intrinsic survival program requires microbiome and immune signaling input
NameZhang, Xiao (author); Friedman, Wilma (chair); Rutgers University; Graduate School - Newark
Date Created2020
Other Date2020-05 (degree)
SubjectStem cells, Biology
Extent1 online resource (xii, 226 pages)
DescriptionBeing one important part of the digestive system, the intestine is responsible for nutrient uptake and for establishing a critical barrier against luminal insults from harsh chemicals or pathogens. Both functions are vital for the survival of the host. Strictly defined architecture of intestinal epithelial cells and the gradient of signaling cues along the villus-crypt axis ensure the maintenance of adult intestinal stem cells, as well as proper regeneration and differentiation of all intestinal epithelial cell types. The Rho family small GTPase Cdc42 controls the proper division of intestinal stem cells and affects subsequent fate-determination of the progenitor cells. How the intestinal epithelium maintains homeostasis and regenerative capacity during constant exposure to genotoxic and pathogenic insults is unclear. We found that ex vivo survival and clonogenicity of intestinal stem cells (ISCs)strictly required Cdc42-mediated response, and Cdc42-deficient enteroids underwent rapid apoptosis. Mechanistically, Cdc42 engaged EGFR and enabled MAPK signaling. Accordingly, mice engineered to have boosted Cdc42-MAPK signaling in ISCs showed enhanced regeneration and were protected from epithelial injury. However, mice with Cdc42-deficient epithelium were viable and maintained functional homeostasis. An ex vivo screen uncovered that a number of inflammatory cytokines restored growth of Cdc42-deficient enteroids. Indeed, intestinal regeneration in mice lacking epithelial Cdc42 was compromised when cytokine-signaling or microbiota sensing was abolished. Antibiotic treatment, IL-22 deficiency, or Stat3 blockage compromised epithelial survival and injury-induced regeneration in mice lacking epithelial Cdc42. Data from this thesis shed lights on how ISC-intrinsic survival programs collaborate with signals from immune and microbiome compartments to provide non-redundant layers of protection for epithelial integrity. We conclude that signaling inputs from microbiome and lamina propria lymphocytes facilitate survival of ISCs with defective survival program. These results suggest that activation of specific epithelial extrinsic signals may benefit intestinal mucosal regeneration in hosts with diminished survival program such as during severe genotoxic or pathogenic injuries.
NotePh.D.
NoteIncludes bibliographical references
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/t3-003d-wh71
LanguageEnglish
CollectionGraduate School - Newark Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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