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

Area of Science:

• Immunology
• Gastroenterology
• Stem Cell Biology

Background:

• Intestinal epithelial regeneration is vital for organ function following injury.
• The intestinal stem cell (ISC) niche regulates normal epithelial maintenance via specific signaling pathways.
• Regulation of the ISC compartment post-intestinal injury remains incompletely understood.

Purpose of the Study:

• To investigate the role of innate lymphoid cells (ILCs) and interleukin-22 (IL-22) in intestinal epithelial regeneration.
• To elucidate the mechanisms by which IL-22 influences intestinal stem cells (ISCs) and promotes tissue repair.

Main Methods:

• Ex vivo intestinal organoid cultures (mouse and human) were used to assess growth.
• Recombinant IL-22 was applied to organoids and in vivo models.
• STAT3 phosphorylation and ATOH1 deficiency were analyzed in relation to IL-22 effects.
• In vivo studies involved allogeneic bone marrow transplantation models.

Main Results:

• ILC-derived IL-22 significantly increased mouse small intestine organoid growth in an IL-22-dependent manner.
• Recombinant IL-22 directly promoted ISC proliferation and expansion in both mouse and human organoids.
• IL-22 induced STAT3 phosphorylation in Lgr5(+) ISCs, which was essential for organoid formation and regeneration.
• In vivo IL-22 treatment improved ISC recovery, epithelial regeneration, and reduced pathology in a graft-versus-host disease model.

Conclusions:

• Interleukin-22 (IL-22) produced by innate lymphoid cells (ILCs) is a key immune mediator supporting intestinal epithelial regeneration.
• IL-22 directly activates intestinal stem cells (ISCs) via STAT3 signaling, promoting proliferation and repair independently of Paneth cells.
• This study reveals a critical immune-to-stem cell communication pathway essential for intestinal healing and reducing disease severity.