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

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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.

Intestinal cells along the crypt–villus axis. The crypt of the intestinal epithelium harbors actively cycling Lgr5+ stem cells at its base, interspersed with Paneth cells, while quiescent stem cells reside at the +4 position of the crypt. Secretory and absorptive progenitors in the transit amplifying (TA) zone become differentiated and migrate up the villus, where they undergo programmed cell death (anoikis). The secretory lineage is comprised of Paneth cells, enteroendocrine cells, and goblet cells, whereas absorptive progenitors give rise to enterocytes.
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Chromatin regulation along the crypt–villus axis. (a) Crypt and villus cells display a high degree of similarity in chromatin patterns, existing in a broadly permissive state. A small subset of loci undergo chromatin remodeling throughout the differentiation process: Enhancers associated with intestinal stem cell (ISC) traits become repressed (H3K27me3, H2AK119ub), while enhancers associated with differentiated cell types become active (H3K4me2, H3K27ac). (b) ISCs maintain enhancers of both secretory and absorptive lineage‐specific genes in a broadly permissive (active) state.
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DNA methylation along the crypt–villus axis. DNA methylation patterns in the intestinal epithelium remain relative stable, with most genomic regions maintaining high levels of methylation in both stem cells and differentiated populations. Some loci experience changes in their methylation status throughout differentiation: Stem cell‐associated markers acquire DNA methylation as they commit to differentiated lineages, while cell‐type‐specific enhancers occlude DNA methylation accumulation in this process.
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Signaling in the crypt niche. Hh ligands are produced by intestinal epithelial cells to activate signaling in mesenchymal cells in a paracrine manner. In response, mesenchymal cells produce BMP ligands, which promote differentiation in the epithelium. To protect the intestinal stem cells (ISCs) from differentiation induced by BMP ligands, mesenchymal cells in close proximity to the ISCs (i.e., crypt base) produce BMP antagonists (GREMLIN1, GREMLIN2, and CHORDIN‐LIKE1). To promote ISC proliferation, WNT ligands are produced by adjacent Paneth cells as well as by the pericryptal mesenchymal cells.
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Hippo signaling interactions. In intestinal stem cells (ISCs; blue cell), Hippo signaling is switched off, which results in the accumulation and subsequent translocation of dephosphorylated YAP/TAZ into the nucleus, where it activates target gene expression through the TEAD transcription factors. Nuclear YAP/TAZ can activate the Wnt pathway and increase nuclear NICD, leading to Notch activation. The activation of TEAD, Wnt, and Notch targets promotes and maintains stem cell function. In differentiated enterocytes (green cell), Hippo signaling remains active, which results in a kinase cascade that phosphorylates YAP/TAZ, sequestering it to the cytoplasm. This cascade leads to the repression of TEAD target genes through the co‐repressor VGLF. Phosphorylated YAP/TAZ has been shown to repress Wnt signaling by inhibiting DVL activity, as well as associating with the β‐CATENIN destruction complex to facilitate degradation. This results in the binding of transcriptional repressor GROUCHO and the inhibition of Wnt target gene expression. The lack of nuclear YAP results in the downregulation of NICD, leading to Notch inhibition. The repression of TEAD, Wnt, and Notch targets promotes and maintains a differentiated state.
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Lateral inhibition by Notch signaling. In the transit‐amplifying (TA) compartment, DELTA‐LIKE (DLL) from a cell (purple) with low Notch activity stimulates Notch signaling in an adjacent cell (green) leading to the activation of Hes1 expression. HES1 represses Atoh1 and Dll ligands, promoting an absorptive progenitor fate. In the Notch low cell, Hes1 is inhibited, leading to the activation of Atoh1 expression. Subsequently, ATOH1 activates the expression of Dll ligands, reinforcing the cell in a Notch low state, while promoting secretory lineage differentiation.
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Spatial distribution of signaling pathways in the crypt–villus axis. Incorporating the current understanding of signaling pathways in the crypt–villus axis, a gradient model has been proposed: Bmp, Hh, and Hippo signaling pathways are most active at the villi, promoting differentiation, and their activity decreases toward the crypts. In contrast, Wnt and Notch signaling are highly active at the base of the crypts, maintaining stem cell renewal. Further experiments, however, are needed to verify this proposed gradient model. Box A: Refer to Figure for lateral inhibition; Box B: Refer to Figure for signaling in the crypt niche.
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Adult Stem Cells, Tissue Renewal, and Regeneration > Tissue Stem Cells and Niches
Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cell Differentiation and Reversion

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