Table 2 Major pathways involved in intestinal epithelial regeneration and repair.
Signaling pathway | (S)timulation/(I)nhibition | Effect | Example of eliciting factor and/or mechanism | Ref. |
|---|---|---|---|---|
mTORC1/SIRT1 | S | ISC expansion | Caloric restriction | |
PI3K/AKT | S | IEC proliferation, G1 cell cycle progression | Binding of EGF, TGF-α | |
WNT/R-spondin/β-catenin | S | ISC proliferation, suppressed IEC differentiation | Arachidonic acid presence | |
STAT5/NFκβ | STAT5 S | ISC proliferation, crypt regeneration | Cytokine receptor activation | |
NFκβ I | Mucosal wound healing | Decreased MLCK phosphorylation and TJ permeability | ||
Hippo/YAP-TAZ | Hippo I, YAP S | Intestinal regeneration in DSS colitis | Binding of stroma-derived Immunoglobulin superfamily containing leucin-rich repeat protein (ISLR) | |
Low Wnt signaling, wound-healing response | ||||
Excessive PC differentiation, crypt regeneration | ||||
Increased organoid growth | Binding of bile acids to TGR5 | |||
Hippo S, YAP I | Maintenance Wnt signaling, canonical stem cell function | – | ||
SMAD | S | Increased barrier function through TJ protein upregulation | Binding of TGF-β | |
BMP/SMAD | I | ISC maintenance, expansion | Relief of direct, HDAC1-mediated transcriptional repression of stem cell signature genes | |
ERK/MAPK | S | ISC expansion, crypt formation, IEC proliferation | Binding of HGF to MET | |
Increased barrier function through TJ protein upregulation | Binding of TGF-β | |||
Enhanced IEC migration | Binding of Flagellin | |||
STAT3 | S | Intestinal mucosa regeneration, organoid formation | Downstream FAK activation and integrin signaling | |
ISC expansion, crypt formation, organoid proliferation | Binding of IL-22 to IL-22R | |||
Myd88/NFκβ | S/I | Regulation of intestinal epithelial integrity and inflammatory responses | NFκβ inhibition leads to severe chronic inflammation and epithelial apoptosis | |
Epithelial MyD88 required for survival in multiple colitis models | ||||
c-Jun/AP-1 | S | Promotion of epithelial restitution after wounding through cell migration | Upregulation of PLCγ1-induced Ca2+ signaling | |
JNK2 | S | Epithelial barrier maintenance, enhanced Goblet cell and EEC differentiation and mucus production | Protection from DSS colitis, reduced barrier dysfunction and enterocyte apoptosis, increased Atoh1 expression |
