Smooth muscle contributes to the development and function of a layered intestinal stem cell niche

Wnt and Rspondin (RSPO) signaling drives proliferation, and bone morphogenetic protein inhibitors (BMPi) impede differentiation, of intestinal stem cells (ISCs). Here, we identify the mouse ISC niche as a complex, multi-layered structure that encompasses distinct mesenchymal and smooth muscle populations. In young and adult mice, diverse sub-cryptal cells provide redundant ISC-supportive factors; few of these are restricted to single cell types. Niche functions refine during postnatal crypt morphogenesis, in part to oppose the dense aggregation of differentiation-promoting BMP+ sub-epithelial myofibroblasts at crypt-villus junctions. Muscularis mucosae, a specialized muscle layer, first appears during this period and supplements neighboring RSPO and BMPi sources. Components of this developing niche are conserved in human fetuses. The in vivo ablation of mouse postnatal smooth muscle increases BMP signaling activity, potently limiting a pre-weaning burst of crypt fission. Thus, distinct and progressively specialized mesen-chymal cells together create the milieu that is required to propagate crypts during rapid organ growth and to sustain adult ISCs.

Automated summary

Wnt and RSPO signaling promote proliferation of intestinal stem cells (ISCs), while BMP inhibitors (BMPi) hinder their differentiation. The ISC niche in mice is a complex structure consisting of different mesenchymal and smooth muscle populations. During postnatal crypt morphogenesis, niche functions evolve to counteract the aggregation of differentiation-promoting cells and are also conserved in human fetuses. Inhibiting smooth muscle in mice leads to increased BMP signaling and limits crypt fission. Thus, specialized mesenchymal cells together create the necessary environment for crypt growth and maintenance of adult ISCs.