PIEZO-dependent mechano-sensing of the niche is essential for intestinal stem cell fate decision and maintenance

Stem cells perceive and respond to biochemical and physical signals to maintain homeostasis. Yet, it remains unclear how stem cells sense mechanical signals from their niche in vivo. Here, we investigated the roles of PIEZO mechanosensitive channels in intestinal stem cell (ISC) niche. By employing mouse genetics and single-cell RNAseq analysis, we revealed the requirement for PIEZO channels in ISC maintenance. In vivo measurement of basement membrane stiffness showed that ISCs reside in a more rigid microenvironment at the bottom of the crypt. Using 3D and 2D organoid systems combined with bioengineered substrates and stretching device, we found that PIEZO sense extracellular mechanical stimuli to modulate ISC function. This study delineates the mechanistic cascade of PIEZO activation that coordinates ISC fate decision and maintenance. Crypt were isolated and pooled from 3 control and Piezo-deleted mice.