Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration

Innate lymphoid cells increase the growth of mouse intestinal organoids via IL-22 production; recombinant IL-22 promotes growth of both mouse and human organoids, and promotes mouse intestinal stem cell (ISC) expansion and ISC-driven organoid growth via a STAT3-dependent pathway and independently of Paneth cells; IL-22 treatment in vivo enhances the recovery of ISCs from intestinal injury. Intestinal repair mechanisms The cellular signals supporting normal epithelial intestine maintenance through regulation of intestinal stem cell (ISC) activity are well characterized, but the signals involved in the regulation of the ISC compartment after damage are still unclear. Alan Hanash and colleagues have found that innate lymphoid cells produce interleukin-22 (IL-22) after injury to increase the growth of mouse intestinal organoids. They further show that recombinant IL-22 promotes ISC expansion in both human and mouse organoids, via a STAT3-dependent pathway and independently of the Paneth cells, which provide for ISC maintenance signals. IL-22 treatment also enhanced the recovery of ISCs from intestinal injury. Epithelial regeneration is critical for barrier maintenance and organ function after intestinal injury. The intestinal stem cell (ISC) niche provides Wnt, Notch and epidermal growth factor (EGF) signals supporting Lgr5 + crypt base columnar ISCs for normal epithelial maintenance 1 , 2 . However, little is known about the regulation of the ISC compartment after tissue damage. Using ex vivo organoid cultures, here we show that innate lymphoid cells (ILCs), potent producers of interleukin-22 (IL-22) after intestinal injury 3 , 4 , increase the growth of mouse small intestine organoids in an IL-22-dependent fashion. Recombinant IL-22 directly targeted ISCs, augmenting the growth of both mouse and human intestinal organoids, increasing proliferation and promoting ISC expansion. IL-22 induced STAT3 phosphorylation in Lgr5 + ISCs, and STAT3 was crucial for both organoid formation and IL-22-mediated regeneration. Treatment with IL-22 in vivo after mouse allogeneic bone marrow transplantation enhanced the recovery of ISCs, increased epithelial regeneration and reduced intestinal pathology and mortality from graft-versus-host disease. ATOH1-deficient organoid culture demonstrated that IL-22 induced epithelial regeneration independently of the Paneth cell niche. Our findings reveal a fundamental mechanism by which the immune system is able to support the intestinal