Nfatc1+ colonic stem cells contribute to regeneration upon colitis

Abstract

Background and aim: Colonic stem cells play important roles in both normal epithelial turnover and injury repair. Lgr5⁺ colonic stem cells are highly susceptible to DSS-induced damage. However, it is still unclear how colonic stem cells regenerate injured epithelium during colitis. Here, we explored the functions of a new population of NFATc1⁺ colonic stem cells in experimental colitis.

Methods: Nfatc1⁺ colonic stem cells were labeled using Nfatc1^CreERT2 ;R26^mTmG reporter mice. Immunostaining assays were used to detect Goblet cells, enteroendocrine cells, and intestinal stem/progenitor cells. We performed lineage tracing assay to investigate whether Nfatc1⁺ cells are real colonic stem cells using Nfatc1^CreERT2 ;R26^mTmG mice. The contribution of Nfatc1⁺ stem cells on epithelial regeneration was detected in experimental colitis induced by DSS.

Results: Nfatc1-reporter marked cells are enriched for +3 to +5 position in colonic crypts, and they are overlapped with Sox9⁺ cells and Hopx⁺ cells that have been identified as stem cells in small intestine. However, Nfatc1-reporter marked cells are not overlapped with Lgr5⁺ colonic stem cells, as well as differentiated goblet cells and enteroendocrine cells. Furthermore, Nfatc1-reporter marked cells are able to give rise to all lineages of the colonic epithelium, and they preferentially contribute to the regeneration of colonic epithelium in DSS-induced experimental colitis.

Conclusion: Nfatc1⁺ cells were identified as a novel population of colonic stem cells that are primarily located at +3 to +5 position and contribute to epithelial regeneration during colitis.

Keywords: Nfatc1; colitis; colonic stem cells; lineage tracing.