Transcriptional regulation of intestinal stem cells and differentiation

The intestinal epithelium is one of the most rapidly self-renewing tissues in the body and thus the ideal tissue for studying somatic progenitor and stem cell biology. The intestinal epithelium is composed of a single layer of cells that contains four major differentiated cell types as well as intestinal stem cells (ISCs) and progenitor cells that replenish differentiated cells throughout life. However, the molecular mechanisms that govern the self-renewal and differentiation of ISCs are only partially understood. Previously, one of the terminally differentiated epithelial cell types, the Paneth cells, were proposed to be the ISC “niche”. However, subsequent studies have found ablation of Paneth cells in mice showed no effect on either stem cell maintenance or proliferation. I have analyzed the poorly understood mesenchymal contribution to epithelial stem cell maintenance and homeostasis by generating Foxl1-hDTR transgenic mice, in which the human diphtheria toxin receptor (hDTR) is placed under the control of the Foxl1 promoter. Foxl1 is exclusively expressed in the subepithelial mesenchyme of the adult gastrointestinal tract. Ablation of Foxl1+ mesenchymal cells resulted in severe weight loss and disruption of epithelial architecture and a dramatic reduction in proliferation of both epithelial stem and transit-amplifying progenitor cells. I found that these effects are caused by the loss of activated Wnt/β-catenin signaling signaling in the epithelium. Taken together, I have identified a novel mesenchymal ISC niche that supports both proliferation and maintenance of stem cells possibly through providing important Wnt ligands