PT - JOURNAL ARTICLE AU - Mara Martín-Alonso AU - Håvard T. Lindholm AU - Sharif Iqbal AU - Pia Vornewald AU - Sigrid Hoel AU - Mirjam J. Damen AU - A.F.Maarten Altelaar AU - Pekka Katajisto AU - Alicia G. Arroyo AU - Menno J. Oudhoff TI - Smooth muscle-specific MMP17 (MT4-MMP) defines the intestinal ECM niche AID - 10.1101/2020.06.18.147769 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.06.18.147769 4099 - http://biorxiv.org/content/early/2020/06/18/2020.06.18.147769.short 4100 - http://biorxiv.org/content/early/2020/06/18/2020.06.18.147769.full AB - Smooth muscle is an essential component of the intestine, both to maintain its structure and produce peristaltic and segmentation movements. However, very little is known about other putative roles that smooth muscle may have. Here, we show that smooth muscle is the dominant supplier of BMP antagonists, which are niche factors that are essential for intestinal stem cell maintenance. Furthermore, muscle-derived factors can render epithelium reparative and fetal-like, which includes heightened YAP activity. Mechanistically, we find that the matrix metalloproteinase MMP17, which is exclusively expressed by smooth muscle, is required for intestinal epithelial repair after inflammation- or irradiation-induced injury. Furthermore, we provide evidence that MMP17 affects intestinal epithelial reprogramming indirectly by cleaving the matricellular protein PERIOSTIN, which itself is able to activate YAP. Together, we identify an important signaling axis that firmly establishes a role for smooth muscle as a modulator of intestinal epithelial regeneration and the intestinal stem cell niche.Competing Interest StatementThe authors have declared no competing interest.