Subepithelial Myofibroblasts Are Critical Regulators of Intestinal Epithelial Restoration

Intestinal epithelial migration is supposed to occur in a passive manner driven by the mitotic pressure exerted either by the cryptal stem cells, under physiological conditions, or the newly formed epithelium, upon damage. However, whether interactions between different neighboring cell types and with the matrix contribute to epithelial movement remain elusive. Here, we developed a novel three-dimensional in vitro intestinal mucosa model of gap closure, that includes both the epithelium and the basement membrane cellular compartments in a spatially relevant manner, to show that intestinal subepithelial myofibroblasts (ISEMFs) play a crucial role in epithelial restoration. ISEMF-derived biochemical cues boost epithelial proliferation and maintain epithelial barrier integrity. While, at the wounded area, ISEMF actively migrate to the epithelial front where they activate and generate ɑ-SMA contractile stress fibers along the direction of the epithelial cells promoting epithelial migration. Furthermore, ISEMF also deposit collagen paths that act as “guide rails” for directing IEC migration. Thus, the mere physical presence of ISEMFs can greatly accelerate restoration in wound healing, which suggests that ISEMFs should be recognized as new potential therapeutic targets. ### Competing Interest Statement The authors have declared no competing interest.