While Wnt signaling is clearly important for the intestinal epithelial homeostasis, the relevance of various sources of Wnt ligands themselves remains incompletely understood. Wnt blockage in distinct stromal cell types suggested obligatory functions of several stromal cell sources and yielded different observations. The physiological contribution of epithelial Wnt to tissue homeostasis remains unclear. We show here that blocking epithelial Wnts affected colonic Reg4+ epithelial cell differentiation, and impaired colonic epithelial regeneration after injury. Single cell RNA analysis of intestinal stroma showed that the majority of Wnt-producing cells were contained in transgelin (Tagln+) and smooth muscle actin alpha 2 (Acta2+) expressing populations. We genetically attenuated Wnt production from these stromal cells using Tagln-Cre and Acta2-CreER drivers, and found that Wnt blockage from either epithelium or Tagln+ and Acta2+ stromal cells impaired colonic epithelial healing after chemical-induced injury. Aggregated Wnt blockage from both epithelium and Tagln+ or Acta2+ stromal cells drastically diminished epithelial repair, increasing morbidity and mortality. These results from two uncharacterized stromal populations suggested that colonic recovery from colitis-like injury depends on multiple Wnt-producing sources.
Colonic healing requires WNT produced by epithelium as well as Tagln+ and Acta2+ stromal cells
These authors contributed equally to this study.
- Award Group:
- Funder(s): National Institutes of Health
- Award Id(s): R01DK102934
- Funder(s):
- Award Group:
- Funder(s): American Cancer Society
- Award Id(s): RSG-15-060-01-TBE
- Funder(s):
- Award Group:
- Funder(s): National Science Foundation
- Award Id(s): 1353890
- Funder(s):
- Award Group:
- Funder(s): Rutgers, The State University of New Jersey
- Award Id(s): IMRT award
- Funder(s):
- Award Group:
- Funder(s): New Jersey Commission on Cancer Research
- Award Id(s): DFHS16PPC045
- Funder(s):
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Soumyashree Das, Qiang Feng, Iyshwarya Balasubramanian, Xiang Lin, Haoran Liu, Oscar Pellόn-Cardenas, Shiyan Yu, Xiao Zhang, Yue Liu, Zhi Wei, Edward M. Bonder, Michael P. Verzi, Wei Hsu, Lanjing Zhang, Timothy C. Wang, Nan Gao; Colonic healing requires WNT produced by epithelium as well as Tagln+ and Acta2+ stromal cells. Development 2021; dev.199587. doi: https://doi.org/10.1242/dev.199587
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