Birth and delineation of the intestinal stem cell niche

Abstract

AbstractWnt and Rspondin (RSPO) signaling triggers proliferation, and bone morphogenetic protein inhibitors (BMPi) impede differentiation, of intestinal stem cells (ISCs). Here we report that the functional ISC niche is a complex, multi-layered mesenchymal structure that includes distinct smooth muscle populations and describe how that niche organizes early in mouse life. Diverse sub-cryptal cells provide redundant supportive factors, with distinct BMPi and the most potent Wnt agonist, RSPO2, restricted to single cell types. Two functionally opposing elements arise in tandem during a critical period of crypt morphogenesis: a prominent shelf of BMP+ sub-epithelial myofibroblasts that promote epithelial differentiation and the muscularis mucosae, a specialized muscle layer generated de novo to supplement other RSPO and BMPi sources. In vivo ablation of smooth muscle, while preserving trophocytes, raises crypt BMP activity and potently limits crypt expansion. Thus, distinct and progressively refined mesenchymal components together create the milieu necessary to propagate crypts during rapid organ growth and to sustain ISCs in the adult niche.