Mechanical strain of the intestinal epithelium directs absorptive lineage maturation

Abstract

The intestinal epithelium is continuously subjected to a variety of mechanical forces, including extrinsic peristaltic contractions and intrinsic tensile forces generated by epithelial cell migration. Yet, how these mechanical cues influence the cellular processes underlying intestinal homeostasis remains poorly understood. In this study, we examine the impact of mechanical forces on intestinal cell dynamics by applying controlled external stretch to intestinal organoids, combined with high-throughput single-cell transcriptomic profiling. Our analyses reveal that prolonged cyclic mechanical strain alters the composition of differentiated intestinal cell populations. Specifically, we identify a strain-induced shift in the absorptive lineage towards a less mature state, with expansion of the population of early-stage enterocytes at the crypt-villus interface. This shift is associated with downregulation of transcriptional programs controlling enterocyte maturation within absorptive precursor populations. Our findings indicate that mechanical strain directs the maturation of the intestinal absorptive lineage, and highlight a role for mechanical forces in shaping intestinal epithelial composition and function.