Crosstalk among Wnt, Notch, EGF/ErbB, and BMP signaling pathways in intestinal stem cell fate

Background Intestinal stem cell (ISC) proliferation and differentiation are tightly regulated by signaling crosstalk to maintain epithelial homeostasis. Objectives This review synthesizes current evidence on the roles and interactions of Wnt, Notch, EGF/ErbB, and BMP pathways in governing ISC maintenance, self-renewal, and lineage fate decisions. Methods This narrative review was synthesized from recent experimentally validated evidence from in vivo (mouse models, knockout/knock-in systems) and in vitro (intestinal organoid cultures, enteroids) studies. Key findings were extracted from research employing CRISPR/Cas9 gene editing, lineage tracing, immunohistochemistry, and pathway-specific activation or inhibition assays. The selection focused on molecular and cellular mechanisms governing the roles and crosstalk of Wnt, Notch, EGF/ErbB, and BMP signaling pathways in regulating intestinal stem cell fate decisions. Results Canonical Wnt signaling maintains ISC stemness and self-renewal, whereas non-canonical Wnt drives cell motility and migration. Notch signaling balances absorptive versus secretory cell fates by modulating ATOH1 expression. Progenitor cells proliferation is further enhanced by EGF and ErbB signaling in synergy with Wnt. Conversely, a spatial BMP gradient suppresses ISC expansion, establishing differential gene expression along the crypt–villus axis. Microenvironmental stress, such as injury, inflammation, and aging, dynamically reshapes Wnt–Notch–EGF/BMP signaling to regulate regeneration and stem cell plasticity. Conclusion Coordinated crosstalk among Wnt, Notch, EGF/ErbB, and BMP pathways forms a dynamic regulatory network that dictates ISC fate, providing strategic targets for regenerative medicine and intestinal disease interventions.