<p>The colonic crypts are principally composed by Lgr5⁺ stem cells and deep crypt secretory (DCS) cells. c-Kit-expressing cells mark DCS cells and supply Wnt3, EGF, and Notch signals to support their neighboring crypt bottom-intermingled Lgr5⁺ cells. However, the role of c-Kit⁺ cells beyond supporting Lgr5⁺ cells in colonic epithelium remains unexplored. Here, we identify that c-Kit⁺ cells are a heterogeneous entity and possess stemness potency to differentiate into the entire spectrum of epithelial cells and renew the homeostatic colon. Intriguingly, c-Kit⁺ cells play a pivotal role in epithelium repair in mouse models of colitis when contemporary Lgr5⁺ cells are insufficient or absent. Depletion of c-Kit⁺ cells or inhibition of SCF/c-Kit signaling worsens, while supplementation of SCF alleviates colonic epithelium injury during colitis. Our findings unravel the fate and function of c-Kit⁺ cells in homeostatic colon and recovery during colonic epithelium injury which has translational implications for human inflammatory bowel diseases.</p><p></p>