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Ablation of colonic epithelial Reg4+ support cells induces Notch-independent regeneration and mesenchymal remodeling

The colonic epithelium harbors a complex network of adult stem cells that integrate signals from many supporting cells to assist in their decision making. In this study, we ablate an epithelial secretory support cell population characterized by Reg4 expression, to investigate the systemic impact on stemness-related cell signaling pathways. Ablation of these cells results in a hyperproliferative state as well as paradoxical activation of Notch signaling, with the proliferative effect continuing even during Notch inhibition. Reg4+ cell ablation also causes an unexpected remodeling of the mesenchyme. We observe increased presence of Pdgfra-high fibroblasts and an expanded network of smooth muscle myofibroblasts, suggesting that Reg4-ablation reorganizes signaling between epithelium and mesenchyme. These changes occur in the absence of any significant immunological inflammatory response. Our data demonstrate that Reg4+ cells are critical directors of homeostatic epithelial-mesenchymal signaling. Further, this ablation model is an in vivo system for probing cell-cell interactions in the colonic stem cell niche. Graphical Abstract