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.

TNFα Induces LGR5+ Stem Cell Dysfunction In Patients With Crohn’s Disease

“…46 Previously, intestinal epithelial repair was studied after acute injury after ablation of LGR5þ ISCs by irradiation, chemotherapeutic agents, or diphtheria toxin. 34,[47][48][49][50] When active ISCs are selectively lost in acute injury models, reserve ISCs become activated and converted to active ISCs. The epithelial repair is completed as the active ISC pool is replenished by reserve ISCs and all epithelial cell types are regenerated.…”

HOPX: A Unique Homeodomain Protein in Development and Tumor Suppression

“…The cells at the +4 position have a unique transcriptional profile, which includes the expression of HOPX [ 26 , 27 ]. These +4 cells have previously been described as part of the resting stem cell population, which rebuilds Lgr5+ CBCs upon injury and has been found to be radiation resistant, implying that they can survive crypt injury and replace their damaged counterparts [ 28 ]. Furthermore, HOPX-positive intestinal stem cells in the +4 locations are resistant to anoikis, a type of apoptosis caused by aberrant cell matrix connections [ 29 ].…”

MTG16 (CBFA2T3) regulates colonic epithelial differentiation, colitis, and tumorigenesis by repressing E protein transcription factors

“…An area of considerable interest in gastrointestinal biology is the link between epithelial differentiation and regeneration 21,114,115 . Although it was long thought that dedicated "reserve" stem cells at the +4/+5 region, marked by expression of genes such as Bmi1 and mTert, replenished the stem cell compartment in intestinal epithelial regeneration, recent data have indicated that these cells are most likely enteroendocrine cells with the ability to de-differentiate into stem cells following injury 8,22 .…”