WNT16b promotes the proliferation and self‐renewal of human limbal epithelial stem/progenitor cells via activating the calcium/calcineurin A/NFATC2 pathway

Xichen Wan; Songjiao Zhao; Yiqin Dai; Jing Zhang; Yan Shen; Lan Gong; Qihua Le

doi:10.1111/cpr.13460

journal article Open Access Mar 27, 2023

WNT16b promotes the proliferation and self‐renewal of human limbal epithelial stem/progenitor cells via activating the calcium/calcineurin A/NFATC2 pathway

Xichen Wan Songjiao Zhao Yiqin Dai Jing Zhang

Yan Shen

Lan Gong Qihua Le

Cell Proliferation Vol. 56 No. 10 · Wiley

View at Publisher Save 10.1111/cpr.13460

Abstract

AbstractOur previous finding revealed that WNT16b promoted the proliferation of human limbal epithelial stem cells (hLESCs) through a β‐catenin independent pathway. Here, we aimed to explore its underlying molecular mechanism and evaluate its potential in the treatment of limbal stem cell deficiency (LSCD). Based on the findings of mRNA‐sequencing, the expression of key molecules in WNT/calcineurin A/NFATC2 signalling pathway was investigated in WNT16b‐co‐incubated hLESCs and control hLESCs. An epithelial wound healing model was established on Wnt16b‐KO mice to confirm the regulatory effect of WNT16b in vivo. The therapeutic potential of WNT16b‐co‐incubated hLESCs was also evaluated in mice with LSCD. Our findings showed that WNT16b bound with Frizzled7, promoted the release of Ca2+ and activated calcineurin A and NFATC2. With the translocation of NFATC2 into cell nucleus and the activation of HDAC3, WDR5 and GCN5L2, the expression of H3K4me3, H3K14ac and H3K27ac in the promoter regions of FoxM1 and c‐MYC increased, which led to hLESC proliferation. The effect of the WNT16b/calcium/calcineurin A/NFATC2 pathway on LESC homeostasis maintenance and corneal epithelial repair was confirmed in Wnt16b‐KO mice. Moreover, WNT16b‐coincubated hLESCs could reconstruct a stable ocular surface and inhibit corneal neovascularization in mice with LSCD. In conclusion, WNT16b enhances the proliferation and maintains the stemness of hLESCs by activating the non‐canonical calcium/calcineurin A/NFATC2 pathway in vitro and in vivo, and accelerates corneal epithelial wound healing.

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References

Details

Published: Mar 27, 2023
Vol/Issue: 56(10)
License: View

Authors

X

Xichen Wan

Department of Ophthalmology Eye, Ear, Nose and Throat Hospital of Fudan University Fudan China

S

Songjiao Zhao

Department of Ophthalmology, Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai China

Y

Yiqin Dai

Department of Ophthalmology Eye, Ear, Nose and Throat Hospital of Fudan University Fudan China; Research Centre Eye, Ear, Nose and Throat Hospital of Fudan University Fudan China

J

Jing Zhang

Department of Ophthalmology Eye, Ear, Nose and Throat Hospital of Fudan University Fudan China; Research Centre Eye, Ear, Nose and Throat Hospital of Fudan University Fudan China

Y

Yan Shen

Department of Ophthalmology Eye, Ear, Nose and Throat Hospital of Fudan University Fudan China

L

Lan Gong

Department of Ophthalmology Eye, Ear, Nose and Throat Hospital of Fudan University Fudan China; Myopia Key Laboratory of Ministry of Health Eye, Ear, Nose and Throat Hospital of Fudan University Fudan China

Q

Qihua Le

Department of Ophthalmology Eye, Ear, Nose and Throat Hospital of Fudan University Fudan China; Research Centre Eye, Ear, Nose and Throat Hospital of Fudan University Fudan China; Myopia Key Laboratory of Ministry of Health Eye, Ear, Nose and Throat Hospital of Fudan University Fudan China

Funding

National Natural Science Foundation of China Award: 81970767

Natural Science Foundation of Shanghai Municipality Award: 19ZR1408200

Cite This Article

Xichen Wan, Songjiao Zhao, Yiqin Dai, et al. (2023). WNT16b promotes the proliferation and self‐renewal of human limbal epithelial stem/progenitor cells via activating the calcium/calcineurin A/NFATC2 pathway. Cell Proliferation, 56(10). https://doi.org/10.1111/cpr.13460

WNT16b promotes the proliferation and self‐renewal of human limbal epithelial stem/progenitor cells via activating the calcium/calcineurin A/NFATC2 pathway

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