Intestinal epithelial plasticity and regeneration via cell dedifferentiation

Abstract

The intestinal epithelium possesses a great capacity of self-renewal under normal homeostatic conditions and of regeneration upon damages. The renewal and regenerative processes are driven by intestinal stem cells (ISCs), which reside at the base of crypts and are marked by Lgr5. As Lgr5+ ISCs undergo fast cycling and are vulnerable to damages, there must be other types of cells that can replenish the lost Lgr5+ ISCs and then regenerate the damage epithelium. In addition to Lgr5+ ISCs, quiescent ISCs at the + 4 position in the crypt have been proposed to convert to Lgr5+ ISCs during regeneration. However, this “reserve stem cell” model still remains controversial. Different from the traditional view of a hierarchical organization of the intestinal epithelium, recent works support the dynamic “dedifferentiation” model, in which various cell types within the epithelium can de-differentiate to revert to the stem cell state and then regenerate the epithelium upon tissue injury. Here, we provide an overview of the cell identity and features of two distinct models and discuss the possible mechanisms underlying the intestinal epithelial plasticity.

The Role of the Intestinal Epithelium in the “Weep and Sweep” Response during Gastro—Intestinal Helminth Infections

“…To fulfill its function the small intestinal epithelium is organized into villi and crypts, enlarging the surface engaged in nutrients absorption [ 31 ] (whereas the large intestine is composed of crypts only). All epithelial cells lining the intestine come from Lgr5+ intestinal stem cells (ISC), but in the case of tissue damage other cells may acquire stem-cell-like phenotypes through dedifferentiation [ 32 ]. Lgr5+ cells reside at the bottom of crypts [ 33 ] constantly renewing the epithelium by differentiating into enterocytes, microfold (M) cells, enteroendocrine cells (EEC), goblet cells, Paneth cells, and tuft cells (TC) lineages.…”

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 relationship between epithelial differentiation and regeneration (4). Although it was long thought that dedicated Bmi1 + or mTert + “reserve” stem cells at the +4/+5 position replenished the stem cell compartment in intestinal epithelial regeneration, recent data indicate that these cells are enteroendocrine cells that can de-differentiate into stem cells following injury (46).…”

Recent advances in tissue stem cells

“…These functions mainly depend on the single-layered intestinal epithelium that forms crypt-villus structures in the small intestine or crypt structures in the large intestine. The intestinal epithelium is composed of several cell types to accomplish multiple functions, including nutrient-absorbing enterocytes, mucus-secreting goblet cells, hormone-producing enteroendocrine cells, chemosensory tuft cells, defending Paneth cells, TA cells, progenitors, stem cells, and other cells of less defined functions, such as microfold cells (de Sousa E Melo and de Sauvage, 2019; Liu and Chen, 2020;Mabbott et al, 2013). Some immune cells (intraepithelial lymphocytes) are also found in the epithelium (McDonald et al, 2018).…”

“…+ stem cells and contribute to the rebuilding of epithelial structures; among them are label-retaining secretory precursors, Alpi + enterocyte precursors, Dll1 + progenitors, Atoh1 + progenitors, enteroendocrine cells, tuft cells, and Paneth cells (Liu and Chen, 2020;Metcalfe et al, 2014; Figure 5).…”