The extracellular matrix controls stem cell specification and tissue morphology in the developing and adult gut

The rapid renewal of the epithelial gut lining is fuelled by stem cells that reside at the base of intestinal crypts. In recent years, the signal transduction pathways and morphogens that regulate intestinal stem cell self-renewal and differentiation have been well characterised. In contrast, although extracellular matrix (ECM) components form an integral part of the intestinal stem cell niche, we only have limited insight into their functional role. Here, we set out to systematically investigate the impact of physiological ECM components on the intestinal epithelium. We found that laminin increased Lgr5+ stem cell and Paneth cell numbers and enabled crypt-like morphology changes, whereas collagen I promoted a fetal-like gene expression program. Moreover, during gut development the ECM is dramatically remodelled by mesenchymal cells, which is accompanied by a specific and local expression of the laminin receptor ITGA6 in the crypt-forming epithelium. Importantly, deletion of laminin in the adult mouse results in a fetal-like epithelium. Therefore, our work uncovers a dominant role of the ECM-epithelial axis in crypt formation and regulation of stem cells in development and homeostasis.