The Intestinal Stem Cell Niche: Homeostasis and Adaptations

Abstract

The intestinal epithelium is a rapidly renewing cellular compartment. This constant regeneration is a hallmark of intestinal homeostasis and requires a tightly regulated balance between intestinal stem cell (ISC) proliferation and differentiation. Since intestinal epithelial cells directly contact pathogenic environmental factors that continuously challenge their integrity, ISCs must also actively divide to facilitate regeneration and repair. Understanding niche adaptations that maintain ISC activity during homeostatic renewal and injury-induced intestinal regeneration is therefore a major and ongoing focus for stem cell biology. Here, we review recent concepts and propose an active interconversion of the ISC niche between homeostasis and injury-adaptive states that is superimposed upon an equally dynamic equilibrium between active and reserve ISC populations.

Keywords: injury; interconversion; intestinal homeostasis; regeneration; stem cell niche.

Figure 1:. Cell types of the small intestine and colon

Numerous well-defined subtypes of epithelial cells can be found in the crypt/villus axis of the small intestine (A) and in the glands of the colon (B). Actively dividing intestinal stem cells (ISCs) are shown in green and TA (transit amplifying) cells are represented in gray. Absorptive enterocytes of the small intestine and colonocytes of the colon share common functions (red). Secretory cells comprise EE (Entereoendocrine) (blue); Goblet (brown); Tuft (purple); quiescent +4 ISCs, which possess enteroendocrine markers (light blue); and Paneth cells (yellow). The red arrows point at the ability of enterocytes, quiescent +4 enteroendocrine cells or Paneth cells to convert to active ISCs.

Figure 2:. ISC dynamics during homeostasis, injury and repair

(A) During intestinal homeostasis, active intestinal stem cells (ISCs) (green) marked by expression of Lgr5, Olfm4 and Ascl2 drive epithelial renewal at the bottom of the crypts neighbored by Paneth cells (yellow). (B) Intestinal injury leads to depletion of actively dividing ISCs, (C) which somehow induces enterocytes (Dll1⁺, Alpi⁺), +4/Enteroendocrine (Bmi1⁺, mTert⁺ or Prox1⁺) or Paneth cells (Liz1⁺) to convert to active ISCs (represented by the red arrows) for epithelial repair.

Figure 3:. Canonical pathways present in the ISC niche

Different niche factors impact the activity of active intestinal stem cells (ISCs) during homeostasis. (A) From the basolateral side, the integrity and function of ISCs is maintained directly or indirectly by “homeostatic niche” factors such as Wnts, R-spondins (Rspo), BMP and Hedgehog, secreted by stromal populations such as telocytes, myofibroblasts and smooth muscle cells; and Notch and redundant Wnt signals secreted by epithelial Paneth cells. The Hippo pathway via YAP may transduce mechanosensory signals. (B) On the apical side, dietary lipids impact directly the activity of ISCs and commensal microbiota contribute to the “homeostatic niche” by producing beneficial signals such as lactate.

Figure 4:. Niche cell changes during injury and repair

Injury to the intestinal epithelium is often accompanied by changes in the microbiota. To aid repair upon injury and return to homeostasis, “injury niche” factors are also provided by cell populations that are dispensable during homeostasis, such as neurons, glial and immune cells.

Figure 5:. Interconversion of ISC niches during homeostasis and repair

Summary table depicting the differences between the homeostatic niche and the injury niche – different cell types come into play upon injury and provide different niche factors that help to repair the epithelial damage and the return to homeostasis. GDNF, glial-derived neurotrophic factor; MDP, muramyl-dipeptide.