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.

Keywords: Intestine; Regeneration; Stem Cells.

Figure 1.. Role of crypt-localized cells in epithelial homeostasis and injury-induced regeneration.

A) Homeostatic renewal of the intestinal epithelium (comprising ISCs, transit-amplifying progenitors, absorptive enterocytes, Paneth, goblet, enteroendocrine, and tuft cells) is mediated by active ISCs (aISC) in the crypt base. A rare pool of ISCs located near the +4 position is maintained in a quiescent state (+4 ISC), making only minimal contributions to the homeostatic maintenance of aISC and renewal of differentiated lineages. B) During injury-induced regeneration, when aISCs are compromised or lost, rISCs become a primary cell source that mediates regeneration. Plastic non-ISC cell types can also contribute to regenerating epithelial tissue (blue arrows), presumably through the generation of an aISC intermediate. The +4 position is an approximation, referring to a region of the crypt from +4 to +7 nuclear positions, counted upward from the bottom-most nucleus in the crypt base.

Figure 2.. Models for Conversion Between aISCs and rISCs.

A) Canonical Wnt signaling mediates self renewal of the aISC pool, which is the predominant source of all differentiated lineages. Conversion between aISCs and rISCs can occur, but is rarely observed under normal physiologic conditions. B) When aISCs are selectively lost after injury, rISCs become activated and convert to aISCs via unclear mechanisms. C) Epithelial repair is achieved as the aISC pool is replenished by rISCs, and regeneration of the full complement of epithelial cell types is completed. The rISC pool at this stage is presumably re-established, though this has not been formally tested. Note: transit-amplifying populations are not shown in this diagram.

Figure 3.. Expression patterns of biomarkers commonly associated with rISCs.

Originally reported biomarker specificity is indicated in dark blue. Marker expression patterns reported afterward are indicated in light blue. It is not clear whether and how gene expression patterns are altered, especially within short time periods, during injury (*).