Signaling and epigenetic mechanisms of intestinal stem cells and progenitors: insight into crypt homeostasis, plasticity, and niches

Abstract

The rapid turnover of intestinal epithelial cells is maintained by a small number of stem cells located in pocket-like gland structures called crypts. While our understanding of the identity and function of intestinal stem cells (ISCs) has rapidly progressed, epigenetic and transcriptional regulation in crypt stem cell and progenitor pools remains an active field of investigation. Surrounded by various types of cells in the stroma, crypt progenitors display high levels of plasticity, harboring the ability to interconvert in the face of epithelial damage. Recent studies analyzing epigenetic patterns of intestinal epithelial cells have provided evidence that plasticity is maintained by a broadly permissive epigenomic state, wherein cell-lineage specification is directed through activation of signaling pathways and transcription factor (TF) expression. New studies also have shown that the ISC niche, which is comprised of surrounding epithelial and mesenchymal tissues, plays a crucial role in supporting the maintenance and differentiation of stem cells by providing contextual information in the form of signaling cascades, such as Wnt, Notch, and Hippo. These cascades ultimately govern TF expression to promote early cell-lineage decisions in both crypt stem cells and progenitors. Highlighting recent studies investigating signaling, transcriptional, and epigenetic mechanisms of intestinal epithelial cells, we will discuss the mechanisms underlying crypt homeostasis, plasticity, and niches. WIREs Dev Biol 2017, 6:e281. doi: 10.1002/wdev.281 For further resources related to this article, please visit the WIREs website.

Trained Immunity Carried by Non-immune Cells

“…Epigenetic modifications and immunometabolic mechanisms would be implicated in the persistence of immunological memory. Moreover, the lifespan of iSCs is longer than professional innate immune cells (Arts et al, 2016b; Hotamisligil, 2017; Smith et al, 2017).…”

Human Milk Oligosaccharides Protect against Necrotizing Enterocolitis by Activating Intestinal Cell Differentiation

“…[28] Depending on the stimulus, intestinal crypts sense the luminal environment and stem cells residing at the base of intestinal crypts differentiate into either secretory cells or absorptive cell types to perform cell-specific responses to stimulants. [29] During the pathogenesis of NEC, the fate and function of both differentiated cell types and non-differentiated progenitors are altered, [30,31] causing epithelial barrier breakdown, bacterial translocation and, ultimately, bowel necrosis. [2] In recent years, mechanistic insights about non-digestible oligosaccharides have extended the use of HMOs beyond their prebiotic effects.…”

“…[2] Normally, regeneration and healing of the intestinal epithelium relies on the architecture of intestinal crypts, where pluripotent Lgr5+ positive stem cells at the crypt base continually renew apoptotic cells at the tip of the villus. [29] We show that HMOs increased HMGCS2 in the intestinal crypts to levels above those observed in healthy pups, increasing a rate-limiting enzyme unique to the intestinal stem cells (ISCs) capacity for self-renewal in response to intestinal injury. [20] This observation was associated with activation of both the mTOR and lipid metabolism pathways, two metabolic programs that favor ISC renewal.…”

In vitro models of intestinal epithelium: Toward bioengineered systems

“…The microenvironment changes along the crypt-villus axis, with abundant proliferative signals in the crypt and differentiation signals increasing along villi in inverse gradients. 20 For example, growth factors that favor stemness, proliferation and self-renewal, such as Wnt, 21 EGF 22 and Notch, 23 are present in decreasing gradients from crypt bottom to the top of villi, while BMP activity, which promotes differentiation, increases along villi. 24 ECM composition also changes along the crypt-villus axis.…”