Regenerative Intestinal Stem Cells Induced by Acute and Chronic Injury: The Saving Grace of the Epithelium?

Abstract

The intestinal epithelium is replenished every 3-4 days through an orderly process that maintains important secretory and absorptive functions while preserving a continuous mucosal barrier. Intestinal epithelial cells (IECs) derive from a stable population of intestinal stem cells (ISCs) that reside in the basal crypts. When intestinal injury reaches the crypts and damages IECs, a mechanism to replace them is needed. Recent research has highlighted the existence of distinct populations of acute and chronic damage-associated ISCs and their roles in maintaining homeostasis in several intestinal perturbation models. What remains unknown is how the damage-associated regenerative ISC population functions in the setting of chronic inflammation, as opposed to acute injury. What long-term consequences result from persistent inflammation and other cellular insults to the ISC niche? What particular "regenerative" cell types provide the most efficacious restorative properties? Which differentiated IECs maintain the ability to de-differentiate and restore the ISC niche? This review will cover the latest research on damage-associated regenerative ISCs and epigenetic factors that determine ISC fate, as well as provide opinions on future studies that need to be undertaken to understand the repercussions of the emergence of these cells, their contribution to relapses in inflammatory bowel disease, and their potential use in therapeutics for chronic intestinal diseases.

Keywords: Wnt; enteroids; inflammatory bowel disease; intestinal epithelium; intestinal stem cells (ISCs).

FIGURE 1

Structure of the intestinal epithelium. The intestinal epithelium is replenished every 3–4 days by rapidly dividing Lgr5⁺ intestinal stem cells (ISCs) in the crypt base that differentiate as they move up the crypt villus axis, until they eventually slough into the lumen. Situated between the small intestinal ISCs are Paneth cells, which are important for providing signaling molecules such as WNT, epidermal growth factor (EGF) and Notch ligands (DLL1, DLL4), which aid in the maturation and differentiation of ISCs to either absorptive (enterocytes), secretory [Goblet cell, enteroendocrine (EE)], or Tuft cell lineages. Just above the IECs, frequently in the “+4” position, are slow cycling, damage resistant cells that express the markers Bmi1, Hopx, mTert, and Lrig1. Located in the transit amplifying zone are Atoh1 and Hopx-expressing mature cell precursors, which give rise to different epithelial lineages during homeostasis, but during damage, have a regenerative function, helping aid in re-establishing damaged epithelia.

FIGURE 2

Epithelial repair response to injury. Recent evidence has suggested that there are two types of regenerative cells that fill in the damaged epithelium after injury. When the intestinal epithelium is damaged, either acutely (e.g., via irradiation), or chronically (e.g., in inflammatory bowel diseases), there can be loss of Lgr5⁺ stem cells in the crypt base. These gaps in the epithelium are filled in with either Lgr5⁺-derived reserve stem cells that can de-differentiate downward, or are +4 cell position-derived, including Hopx and/or Atoh1 expressing mature cell precursors that de-differentiate and migrate down from the TA zone to regenerate the stem cell niche.

FIGURE 3

Potential for use of intestinal organoids as “grafts” for the damaged epithelium. Recent advances in epithelial regeneration via organoid transplantation have shown that it could be possible to recover a damaged intestine or colon with autologous organoid transplantation. One approach to improve efficacy in engraftment and recovery post damage would be to isolate intestinal stem cells (ISCs) from the inflamed tissue, or if possible, non-inflamed adjacent tissue, modify target genes via CRISPR or equivalent recombinant techniques, expand the modified ISCs in vitro, and engraft back into the damaged area to recover the injured area. Tissue scaffolds, either synthetic or derived from human intestinal resections, could facilitate growth and proper cellular alignment.