Interleukin-22 Promotes Intestinal Stem Cell-Mediated Epithelial Regeneration

By C. Lindemans, Marco Calafiore, Anna Mertelsmann, Margaret H. O’Connor, J. Dudakov, Robert R. Jenq, E. Velardi, L. Young, O. Smith, Gillian Lawrence and 17 more. Nature, 2015

1,011 citations recorded by the source corpus.

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. 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, 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 epithelium, activating ISCs to promote regeneration.

Subfields: Genetics, Immunology

View Paper: https://www.semanticscholar.org/paper/475ce6daa94fcc5cacebace75cf8b6bda865ae0c

Citations in the corpus

• Stem Cell Organoid Engineering (2016, neutral): “In addition, modeling intestinal diseases often requires the presence of additional tissues of the intestine (i.e., immune cells and mesenchymal cells) and their interactions, which may have important disease implications (Lindemans et al., 2015).”
• Innate Lymphoid Cells: 10 Years On. (2018, neutral): “In addition, IL-22 stabilizes the epithelial barrier by protecting epithelial cells and Lgr5 stem cells from apoptosis induced by irradiation, chemotherapy or graft versus host disease through the activation of STAT3 (Aparicio-Domingo et al., 2015; Lindemans et al., 2015).”