WNT16B enhances the proliferation and self-renewal of limbal epithelial cells via CXCR4/MEK/ERK signaling

Zhao, Songjiao; Wan, Xichen; Dai, Yiqin; Gong, Lan; Le, Qihua

doi:10.1016/j.stemcr.2022.03.001

Cited by 14 publications

(10 citation statements)

References 45 publications

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“…DKK1 and FEZ1 were mainly expressed in the limbal region but not in the differentiated corneal epithelium. This centripetal pattern of decreasing expression has also been observed for other genes essential for the human cornea, including p63 and Lrig1 37–39 …”

Section: Discussionsupporting

confidence: 65%

“…This centripetal pattern of decreasing expression has also been observed for other genes essential for the human cornea, including p63 and Lrig1. [37][38][39] FEZ1 has been reported to be a multifunctional protein. Previous data demonstrated that FEZ1 participated in axon outgrowth, fasciculation, microtubular transport, and innate-immune pathways [40][41][42][43] but has yet to be associated with stem cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

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Single‐cell transcriptomics implicates the FEZ1–DKK1 axis in the regulation of corneal epithelial cell proliferation and senescence

Zhu

Wang

et al. 2023

Cell Proliferation

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Limbal stem/progenitor cells (LSC) represent the source of corneal epithelium renewal. LSC proliferation and differentiation are essential for corneal homeostasis, however, the regulatory mechanism remains largely unexplored. Here, we performed single‐cell RNA sequencing and discovered proliferation heterogeneity as well as spontaneously differentiated and senescent cell subgroups in multiply passaged primary LSC. Fasciculation and elongation protein zeta 1 (FEZ1) and Dickkopf‐1 (DKK1) were identified as two significant regulators of LSC proliferation and senescence. These two factors were mainly expressed in undifferentiated corneal epithelial cells (CECs). Knocking down the expression of either FEZ1 or DKK1 reduced cell division and caused cell cycle arrest. We observed that DKK1 acted as a downstream target of FEZ1 in LSC and that exogenous DKK1 protein partially prevented growth arrest and senescence upon FEZ1 suppression in vitro. In a mouse model of corneal injury, DKK1 also rescued the corneal epithelium after recovery was inhibited by FEZ1 suppression. Hence, the FEZ1–DKK1 axis was required for CEC proliferation and the juvenile state and can potentially be targeted as a therapeutic strategy for promoting recovery after corneal injury.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Single‐cell transcriptomics implicates the FEZ1–DKK1 axis in the regulation of corneal epithelial cell proliferation and senescence

Zhu

Wang

et al. 2023

Cell Proliferation

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“…Our previous work showed that exogenous WNT16b (200 ng/mL) enhanced the proliferation of hLESCs (Figure S2A–E) in a β‐catenin‐independent manner 9 . Based on our previous work, mRNA sequencing was performed to detect which non‐canonical WNT pathway was involved.…”

Section: Resultsmentioning

confidence: 99%

“…The expression of WNT16b has mainly been found in the basal layer of the limbal epithelium, 12 which is generally believed to be the location of hLESCs 13 . Our previous study found that WNT16b enhanced the proliferation and self‐renewal of hLESCs, and this effect was not dependent on the canonical β‐catenin pathway 9 . Among non‐canonical WNT pathways, the WNT‐Ca 2+ pathway participates in the regulation of proliferation, self‐renewal and differentiation in various stem cells 5,14,15 .…”

Section: Introductionmentioning

confidence: 95%

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

et al. 2023

Self Cite

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Our 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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“…Gastrointestinal epithelial cell activities, such as survival, migration, and proliferation could be regulated via stimulating CXCR4/ERK signaling pathway. It has been reported that WINT16B (a secreted protein that could activate both canonical and non-canonical WNT signaling pathways) could enhance the proliferation and self-renewal of corneal epithelial cells, and accelerate corneal epithelial wound healing through CXCR4/ERK signaling cascade (Zhao et al 2022 ). Stromal cell-derived factor/chemokines-12 could regulate the maturation and restoration of the intestinal epithelial cells via CXCR4/ERK signaling pathway, and restore the integrity of the mucosal barrier in vivo (Zimmerman et al 2011 ).…”

Section: Discussionmentioning

confidence: 99%

Human TFF2-Fc fusion protein alleviates DSS-induced ulcerative colitis in C57BL/6 mice by promoting intestinal epithelial cells repair and inhibiting macrophage inflammation

et al. 2023

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The clinical drugs for ulcerative colitis mainly affect the inflammatory symposiums with limited outcomes and various side effects. Repairing the damaged intestinal mucosa is a promising and alternative strategy to treat ulcerative colitis. Trefoil factor family 2 (TFF2) could repair the intestinal mucosa, however, it has a short half-life in vivo. To improve the stability of TFF2, we have prepared a new fusion protein TFF2-Fc with much stability, investigated the therapeutic effect of TFF2-Fc on ulcerative colitis, and further illustrated the related mechanisms. We found that intrarectally administered TFF2-Fc alleviated the weight loss, the colon shortening, the disease activity index, the intestinal tissue injury, and the lymphocyte infiltration in dextran sulfate sodium (DSS)-induced colitis mice. In vitro, TFF2-Fc inhibited Caco2 cells injury and apoptosis, promoted cellular migration, and increased the expression of Occludin and ZO-1 by activating P-ERK in the presence of H 2 O 2 or inflammatory conditioned medium (LPS-RAW264.7/CM). Moreover, TFF2-Fc could reduce lipopolysaccharide (LPS)-induced production of inflammation cytokines and reactive oxygen species in RAW264.7 cells, and also inhibits the polarization of RAW264.7 cells to M1 phenotype by reducing glucose consumption and lactate production. Taken together, in this work, we have prepared a novel fusion protein TFF2-Fc, which could alleviate ulcerative colitis in vivo via promoting intestinal epithelial cells repair and inhibiting macrophage inflammation, and TFF2-Fc might serve as a promising ulcerative colitis therapeutic agent.

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WNT16B enhances the proliferation and self-renewal of limbal epithelial cells via CXCR4/MEK/ERK signaling

Cited by 14 publications

References 45 publications

Single‐cell transcriptomics implicates the FEZ1–DKK1 axis in the regulation of corneal epithelial cell proliferation and senescence

Single‐cell transcriptomics implicates the FEZ1–DKK1 axis in the regulation of corneal epithelial cell proliferation and senescence

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

Human TFF2-Fc fusion protein alleviates DSS-induced ulcerative colitis in C57BL/6 mice by promoting intestinal epithelial cells repair and inhibiting macrophage inflammation

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