Reserve Stem Cells in Intestinal Homeostasis and Injury

Abstract

Renewal of the intestinal epithelium occurs approximately every week and requires a careful balance between cell proliferation and differentiation to maintain proper lineage ratios and support absorptive, secretory, and barrier functions. We review models used to study the mechanisms by which intestinal stem cells (ISCs) fuel the rapid turnover of the epithelium during homeostasis and might support epithelial regeneration after injury. In anatomically defined zones of the crypt stem cell niche, phenotypically distinct active and reserve ISC populations are believed to support homeostatic epithelial renewal and injury-induced regeneration, respectively. However, other cell types previously thought to be committed to differentiated states might also have ISC activity and participate in regeneration. Efforts are underway to reconcile the proposed relatively strict hierarchical relationships between reserve and active ISC pools and their differentiated progeny; findings from models provide evidence for phenotypic plasticity that is common among many if not all crypt-resident intestinal epithelial cells. We discuss the challenges to consensus on ISC nomenclature, technical considerations, and limitations inherent to methodologies used to define reserve ISCs, and the need for standardized metrics to quantify and compare the relative contributions of different epithelial cell types to homeostatic turnover and post-injury regeneration. Increasing our understanding of the high-resolution genetic and epigenetic mechanisms that regulate reserve ISC function and cell plasticity will help refine these models and could affect approaches to promote tissue regeneration after intestinal injury.

Erythroid differentiation regulator-1 induced by microbiota in early life drives intestinal stem cell proliferation and regeneration

“…Taken together, these results demonstrate that Erdr1 stimulates in vitro intestinal epithelial wound closure in mouse and human cells. highly sensitive to DNA damage caused by radiation 39 , and the self-renewal capacity of Lgr5 + ISCs is key to recovery 40,41 . Based on our findings that Erdr1 increased the number of Lgr5 + ISCs and promoted TA cell proliferation in the steady state, we explored whether Erdr1 could mediate similar effects in vivo following radiation-induced injury.…”

Interleukin-10 expands transit-amplifying cells while depleting Lgr5+ stem cells via inhibition of Wnt and notch signaling

“…As active proliferating ISCs (aISCs), CBC cells constantly self-renew and generate all differentiated intestinal lineages, mediating the normal homeostatic turnover of the intestinal epithelium. However, + 4 LRCs, either as nonproliferating or slowly proliferating reserve ISCs (rISCs), usually perform regeneration tasks under tissue damage or extreme physiological stress conditions (3). The periodic renewal of intestinal epithelial cells depends largely on the self-renewal of ISCs, and gradually differentiates into mature intestinal epithelial cells along the villi axis.…”

Wnt Signaling Mediates the Aging-Induced Differentiation Impairment of Intestinal Stem Cells

“…Second, radiation and cytotoxic therapies cause massive loss of ISCs and epithelial cells, which results in complications such as infections and diarrhea. After the acute phase of cell loss, the remaining ISCs rebuild the stem cell pool and the intestinal epithelium via proliferation and differentiation [ 9 ]. Taken together, the maintenance of intestinal homeostasis relies on balanced self-renewal, proliferation and differentiation of ISCs, which play essential roles in intestinal tumor development and regeneration after injury.…”