Microenvironmental control of stem cell fate in intestinal homeostasis and disease

Abstract

The conventional model of intestinal epithelial architecture describes a unidirectional tissue organizational hierarchy with stem cells situated at the crypt base and daughter cells proliferating and terminally differentiating as they progress along the vertical (crypt–luminal) axis. In this model, the fate of a cell that has left the niche is determined and its lifespan limited. Evidence is accumulating to suggest that stem cell control and daughter cell fate determination is not solely an intrinsic, cell autonomous property but is heavily influenced by the microenvironment including paracrine, mesenchymal, and endogenous epithelial morphogen gradients. Recent research suggests that in intestinal homeostasis, stem cells transit reversibly between states of variable competence in the niche. Furthermore, selective pressures that disrupt the homeostatic balance, such as intestinal inflammation or morphogen dysregulation, can cause committed progenitor cells and even some differentiated cells to regain stem cell properties. Importantly, it has been recently shown that this disruption of cell fate determination can lead to somatic mutation and neoplastic transformation of cells situated outside the crypt base stem cell niche. This paper reviews the exciting developments in the study of stem cell dynamics in homeostasis, intestinal regeneration, and carcinogenesis, and explores the implications for human disease and cancer therapies. © 2015 Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Cell Adhesion Molecule CD166/ALCAM Functions Within the Crypt to Orchestrate Murine Intestinal Stem Cell Homeostasis

“…Despite an intense focus on ISC dynamics during the past 10 years,7, 8, 11, 16 an understanding of how distinct stem cell populations are differentially and coordinately regulated is not clear. Although there are studies describing stem cells as harboring intrinsic regulatory programs, 17 it is suggested that the dominant influence derives from the niche 18, 19…”

Comprehensive site-specific whole genome profiling of stromal and epithelial colonic gene signatures in human sigmoid colon and rectal tissue

“…Thus, colonic biopsies represent intestinal-specific transcriptional patterns consisting of signals originating from stromal and epithelial cells (7,12,24). To dissect the role of epithelial and stromal genes in intestinal homeostasis, we recently demonstrated in an NSAID clinical trial that the expression of genes involved in cell signaling, cellular movement, and cancer differed significantly [P Ͻ 0.01, false discovery rate (FDR) Ͻ0.001] in the epithelium and stroma (53).…”

Recent Advances in Intestinal Stem Cells

“…The ISC niche is a major regulator of ISC homeostasis and comprises several cell types that are found in the crypt region including: Paneth (deep crypt cells in colon), stromal/myofibroblast and immune cells [26, 27] (Figure 2). Paneth cells in the small intestine are capable of secreting signals for ISC health (Wnt3, EGF, Notch receptor ligands).…”

“…The lamina propria also contains immune cells that contribute to the regulation of ISCs. Most notably, immune cells secrete cytokines such as IL-6 and IL-17 which can stimulate ISC proliferation [26]. Recently it has been shown that inhibition of IL-6 signaling (via a neutralizing antibody) can prevent inflammation-induced ISC proliferation [36].…”