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c-Kit+ cells that intercalate with crypt Lgr5+ cells are distinctively multipotent in colonic epithelium renewal and repair

Cell Death & Differentiation volume 32, pages 1244–1258 (2025)Cite this article

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Abstract

The colonic crypts are principally composed by Lgr5+ stem cells and deep crypt secretory (DCS) cells. c-Kit-expressing cells mark DCS cells and supply Wnt3, EGF, and Notch signals to support their neighboring crypt bottom-intermingled Lgr5+ cells. However, the role of c-Kit+ cells beyond supporting Lgr5+ cells in colonic epithelium remains unexplored. Here, we identify that c-Kit+ cells are a heterogeneous entity and possess stemness potency to differentiate into the entire spectrum of epithelial cells and renew the homeostatic colon. Intriguingly, c-Kit+ cells play a pivotal role in epithelium repair in mouse models of colitis when contemporary Lgr5+ cells are insufficient or absent. Depletion of c-Kit+ cells or inhibition of SCF/c-Kit signaling worsens, while supplementation of SCF alleviates colonic epithelium injury during colitis. Our findings unravel the fate and function of c-Kit+ cells in homeostatic colon and recovery during colonic epithelium injury which has translational implications for human inflammatory bowel diseases.

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Fig. 1: Single-cell expression survey of colonic epithelial cells.
Fig. 2: The lineage tracing of c-Kit+ cells in colonic epithelium.
Fig. 3: The proliferation and stemness of c-Kit+ cells are enhanced during colonic epithelium injury.
Fig. 4: The distinction between c-Kit+ cells and Lgr5+ cells during colonic epithelium renewal and repair.
Fig. 5: c-Kit+ cells ablation disrupts colonic epithelium renewal and delays repair during injury.
Fig. 6: Inhibition of c-Kit signaling delays colonic epithelium repair.
Fig. 7: SCF promotes colonic epithelium repair in irradiation-induced colitis.

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Funding

Science Foundation of Sichuan (No. 2023NSFSC1613, to Y.S.) Science Foundation of Sichuan (No. 2023NSFSC2627, to Q.X.) Postdoctoral Foundation of West China Hospital, Sichuan University (No. 2023HXBH020, to Q.X.) Sichuan Province Science and Technology Scheme - Key R & D Project (the second batch of provincial projects [Gaoxin District] in 2021-72).

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Author notes

  1. These authors contributed equally: Qing Xu, Yuting Zeng, Lan Jiang.

Authors and Affiliations

  1. Department of Pathology and Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, China

    Qing Xu, Yuting Zeng, Zhenru Wu & Yujun Shi

  2. West China Biobank, West China Hospital, Sichuan University, Chengdu, China

    Lan Jiang, Shujun Li & Wei Huang

  3. Department of General Surgery, Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China

    Yongjie Zhou & Jiayin Yang

  4. West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China

    Shiyu Liu & Wei Huang

  5. Institutes for Systems Genetics & Immunology and Inflammation, Frontiers Science Centre for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China

    Shiyu Liu & Wei Huang

  6. Department of Gastroenterology and Hepatology, West China Hospital, Chengdu, China

    Ruoting Men

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  1. Qing Xu
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Contributions

Conceptualization: Y.S., W.H., and J.Y.; Data curation: Y.S., and Q.X.; Formal analysis: Y.S. and Q.X.; Funding acquisition: Y.S., and W.H.; Investigation: Q.X., Y.Z., L.J., Y. Zhou, S. Liu., and S.Li.; Methodology: Y.Zhou, Y.C., and Z.W.; Project administration: Q.X., Y.S., W.H., and J.Y.; Resources: R.M., Y.S., W.H., and J.Y.; Supervision: Y.S., W.H., and J.Y.; Validation: Q.X. and Y.Z.; Visualization: Q.X., and Y.S.; Writing – original draft: Q.X., L.J., Y.S., and W.H.; Writing – review & editing: Y.Z. and J.Y.

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Correspondence to Jiayin Yang, Wei Huang or Yujun Shi.

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Xu, Q., Zeng, Y., Jiang, L. et al. c-Kit+ cells that intercalate with crypt Lgr5+ cells are distinctively multipotent in colonic epithelium renewal and repair. Cell Death Differ 32, 1244–1258 (2025). https://doi.org/10.1038/s41418-025-01471-1

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