2. Academic Validation
  3. Interleukin 22 Expands Transit-Amplifying Cells While Depleting Lgr5+ Stem Cells via Inhibition of Wnt and Notch Signaling

Interleukin 22 Expands Transit-Amplifying Cells While Depleting Lgr5+ Stem Cells via Inhibition of Wnt and Notch Signaling

  • Cell Mol Gastroenterol Hepatol. 2019;7(2):255-274. doi: 10.1016/j.jcmgh.2018.09.006.
Juan-Min Zha 1,  Hua-Shan Li 2,  Qian Lin 2,  Wei-Ting Kuo 3,  Zhi-Hui Jiang 2,  Pei-Yun Tsai 4,  Ning Ding 2,  Jia Wu 2,  Shao-Fang Xu 2,  Yi-Tang Wang 4,  Jian Pan 5,  Xiu-Min Zhou 2,  Kai Chen 2,  Min Tao 2,  Matthew A Odenwald 4,  Atsushi Tamura 6,  Sachiko Tsukita 6,  Jerrold R Turner 7,  Wei-Qi He 8
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Suda (CAM-SU) Genome Resource Center, Soochow University, and Department of Oncology, First Affiliated Hospital of Soochow University, Suzhou, China; Department of Pathology, University of Chicago, Chicago, Illinois.
  • 2 Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Suda (CAM-SU) Genome Resource Center, Soochow University, and Department of Oncology, First Affiliated Hospital of Soochow University, Suzhou, China.
  • 3 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
  • 4 Department of Pathology, University of Chicago, Chicago, Illinois.
  • 5 Institute of Pediatrics, Children's Hospital of Soochow University, Suzhou, China.
  • 6 Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka, Japan.
  • 7 Department of Pathology, University of Chicago, Chicago, Illinois; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: jrturner@bwh.harvard.edu.
  • 8 Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Suda (CAM-SU) Genome Resource Center, Soochow University, and Department of Oncology, First Affiliated Hospital of Soochow University, Suzhou, China; Department of Pathology, University of Chicago, Chicago, Illinois. Electronic address: whe@suda.edu.cn.
PMID: 30686779 DOI: 10.1016/j.jcmgh.2018.09.006
Abstract

Background & aims: Epithelial regeneration is essential for homeostasis and repair of the mucosal barrier. In the context of infectious and immune-mediated intestinal disease, interleukin (IL) 22 is thought to augment these processes. We sought to define the mechanisms by which IL22 promotes mucosal healing.

Methods: Intestinal stem cell cultures and mice were treated with recombinant IL22. Cell proliferation, death, and differentiation were assessed in vitro and in vivo by morphometric analysis, quantitative Reverse Transcriptase polymerase chain reaction, and immunohistochemistry.

Results: IL22 increased the size and number of proliferating cells within enteroids but decreased the total number of enteroids. Enteroid size increases required IL22-dependent up-regulation of the tight junction cation and water channel claudin-2, indicating that enteroid enlargement reflected paracellular flux-induced swelling. However, claudin-2 did not contribute to IL22-dependent enteroid loss, depletion of Lgr5+ stem cells, or increased epithelial proliferation. IL22 induced stem cell Apoptosis but, conversely, enhanced proliferation within and expanded numbers of transit-amplifying cells. These changes were associated with reduced Wnt and Notch signaling, both in vitro and in vivo, as well as skewing of epithelial differentiation, with increases in Paneth cells and reduced numbers of enteroendocrine cells.

Conclusions: IL22 promotes transit-amplifying cell proliferation but reduces Lgr5+ stem cell survival by inhibiting Notch and Wnt signaling. IL22 can therefore promote or inhibit mucosal repair, depending on whether effects on transit-amplifying or stem cells predominate. These data may explain why mucosal healing is difficult to achieve in some inflammatory bowel disease patients despite markedly elevated IL22 production.

Keywords

Enteroid; Interleukin 22; Intestinal Stem Cell; Regeneration; Transit-Amplifying Cell; claudin-2; notch; tight junction; wnt.

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