Microbial and Immune Control of Intestinal Stem Cells

• Author / Creator

  Ferguson, Meghan P

• Intestinal epithelial damage and homeostatic cell shedding sends evolutionarily conserved growth signals to activate division programs in stem cells, which renews the epithelium to maintain barrier integrity. In addition to conserved growth and stress signaling, microbes and innate immune pathways regulate stem cell function during homeostasis and disease. For instance, the microbiome promotes stem cell proliferation and differentiation while overactive innate immune signaling causes stem cell hyperproliferation and exacerbates tumorigenesis. It is clear bacteria and immune pathways are important regulators of stem cell function, however the complexity of the microbiome has made it difficult to elucidate the specific effects individual bacterial species have on stem cells. In addition, the intestine is a heterologous tissue composed of multiple different specialized cell types, including intestinal stem cells, absorptive enterocytes and secretory enteroendocrine cells. Given the heterogeneity of cell types in the intestine and the limitations of vertebrate genetics, cell-type specific contributions of immune pathway activation on intestinal growth have been hard to determine, especially the impact of immune activity in stem cells.
  To determine how individual bacterial species and immune pathways impact stem cell function I used Drosophila melanogaster as a model system. Drosophila provides a number of advantages for this work. For example, Drosophila can be easily reared without a microbiome and associated with single bacterial species to determine their effects. In addition, Drosophila genetics allow for the perturbation of immune signaling in distinct cell types of the intestine, including stem cells. Using Drosophila, I identified the commensal bacteria Lactobacillus brevis as a potent stimulator of stem cell divisions and tumorigenesis. L. brevis altered the expression and intracellular localization of integrins in stem cells, leading to symmetric stem cell expansion. Next, I asked what
  the consequences of immune signaling in stem cells are by activating or inhibiting the immune deficiency (IMD) pathway. Activation of IMD in progenitor cells resulted in intestinal hyperplasia and exacerbation of tumorigenesis. Furthermore, inhibition of IMD reduced homeostatic proliferation and disrupted differentiation. Finally, I asked if the NF-kB family transcription factor Relish acts in stem cells to modulate damage response. Damage of the intestine results in elevated stem cell divisions to repair the injury. However, stem cell specific Relish depletion caused stem cells and their progeny to undergo apoptosis, rendering intestines incapable of effective epithelial repair, leading to host lethality. Thus, bacterial species can have profound effects on stem cell physiology and that immune pathways act directly in stem cells to modify proliferation, tumorigenesis, differentiation and epithelial repair responses.

• Subjects / Keywords

  • Intestine
  • Stem cell
  • immunity
  • Drosophila
  • microbiome

• Graduation date

  Spring 2023

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-6far-9502

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.