The common YAP activation mediates corneal epithelial regeneration and repair with different-sized wounds

Li, Yijian; Ge, Lingling; Xia, Chen; Mao, Yumei; Gu, Xianliang; Ren, Bing; Zeng, Yuxiao; Chen, Min; Chen, Siyu; Liu, Jinhua; Yang, Yujie; Xu, Haiwei

doi:10.1038/s41536-021-00126-2

Cited by 14 publications

(14 citation statements)

References 46 publications

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“…Cell proliferation is often regarded as a key element in wound closure. That said, we and others have previously reported that corneal wound closure occurs in a mater of days in mice 9 , 17 , 22 and in rabbits 50 , 51 , despite the fact that in mice, this phenomenon has been reported as being independent of cell proliferation induction 9 . Interestingly, our results from EdU labeling show that, unlike in mice, in zebrafish cell proliferation is induced quickly after wounding.…”

Section: Discussionmentioning

confidence: 74%

“…Some reports, however, have indicated potential in the central corneal cells to resolve epithelial injuries 18 and to replenish the stem cell pool after limbal injury 19 . More detailed analysis on corneal epithelial cell populations 20 , 21 , and the impact of the magnitude of the injury 22 , are providing new insigths in the mechanisms of corneal wound healing. An elegant study demonstrated that the dynamics of epithelial renewal are similar in zebrafish and mammalian cornea 23 .…”

Section: Introductionmentioning

confidence: 99%

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Unilateral zebrafish corneal injury induces bilateral cell plasticity supporting wound closure

Ikkala

Stratoulias

Michon

2022

Sci Rep

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The cornea, transparent and outermost structure of camera-type eyes, is prone to environmental challenges, but has remarkable wound healing capabilities which enables to preserve vision. The manner in which cell plasticity impacts wound healing remains to be determined. In this study, we report rapid wound closure after zebrafish corneal epithelium abrasion. Furthermore, by investigating the cellular and molecular events taking place during corneal epithelial closure, we show the induction of a bilateral response to a unilateral wound. Our transcriptomic results, together with our TGF-beta receptor inhibition experiments, demonstrate conclusively the crucial role of TGF-beta signaling in corneal wound healing. Finally, our results on Pax6 expression and bilateral wound healing, demonstrate the decisive impact of epithelial cell plasticity on the pace of healing. Altogether, our study describes terminally differentiated cell competencies in the healing of an injured cornea. These findings will enhance the translation of research on cell plasticity to organ regeneration.

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Section: Discussionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Unilateral zebrafish corneal injury induces bilateral cell plasticity supporting wound closure

Ikkala

Stratoulias

Michon

2022

Sci Rep

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“…In addition to self-renewal and stratification, wound healing represents one of the critical functions of healthy CE. In the case of minor wounds, the repair of surface CE is thought to be carried out without recruitment of LSCs, while excessive injuries require compensatory proliferation of LSCs and their transiently amplifying cell (TAC) progeny [ 2 , 32 ]. In many epithelial tissues including CE, nucleotide-induced increase of cytosolic calcium (Ca 2+ ) is known to act as the main initiator to the complex wound healing cascades [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

Corneal epithelial differentiation of human pluripotent stem cells generates ABCB5+ and ∆Np63α+ cells with limbal cell characteristics and high wound healing capacity

et al. 2021

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Background Differentiation of functional limbal stem cells (LSCs) from human pluripotent stem cells (hPSCs) is an important objective which can provide novel treatment solutions for patients suffering from limbal stem cell deficiency (LSCD). Yet, further characterization is needed to better evaluate their immunogenicity and regenerative potential before clinical applications. Methods Human PSCs were differentiated towards corneal fate and cryopreserved using a clinically applicable protocol. Resulting hPSC-LSC populations were examined at days 10–11 and 24–25 during differentiation as well as at passage 1 post-thaw. Expression of cornea-associated markers including PAX6, ABCG2, ∆Np63α, CK15, CK14, CK12 and ABCB5 as well as human leukocyte antigens (HLAs) was analyzed using immunofluorescence and flow cytometry. Wound healing properties of the post-thaw hPSC-LSCs were assessed via calcium imaging and scratch assay. Human and porcine tissue-derived cultured LSCs were used as controls for marker expression analysis and scratch assays at passage 1. Results The day 24–25 and post-thaw hPSC-LSCs displayed a similar marker profile with the tissue-derived LSCs, showing abundant expression of PAX6, ∆Np63α, CK15, CK14 and ABCB5 and low expression of ABCG2. In contrast, day 10–11 hPSC-LSCs had lower expression of ABCB5 and ∆Np63α, but high expression of ABCG2. A small portion of the day 10–11 cells coexpressed ABCG2 and ABCB5. The expression of class I HLAs increased during hPSC-LSCs differentiation and was uniform in post-thaw hPSC-LSCs, however the intensity was lower in comparison to tissue-derived LSCs. The calcium imaging revealed that the post-thaw hPSC-LSCs generated a robust response towards epithelial wound healing signaling mediator ATP. Further, scratch assay revealed that post-thaw hPSC-LSCs had higher wound healing capacity in comparison to tissue-derived LSCs. Conclusions Clinically relevant LSC-like cells can be efficiently differentiated from hPSCs. The post-thaw hPSC-LSCs possess functional potency in calcium responses towards injury associated signals and in wound closure. The developmental trajectory observed during hPSC-LSC differentiation, giving rise to ABCG2+ population and further to ABCB5+ and ∆Np63α+ cells with limbal characteristics, indicates hPSC-derived cells can be utilized as a valuable cell source for the treatment of patients afflicted corneal blindness due to LSCD. Graphical Abstract

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“…DIANA-TarBase and microT-CDS algorithms (genes union function) were used to identify experimentally supported and predicted miRNA/target-mRNA interactions, respectively, as well as significant KEGG pathways, in which target genes were involved ( Table 2 and Table 3 ). Among them emerged the ECM-receptor interaction and the focal adhesion pathways, already described in cornea homeostasis and normal physiological functions [ 27 ], corneal epithelial cell motility [ 28 ], neovascularization [ 29 ] and adhesion [ 30 , 31 ], the Hippo signaling pathway, playing a role in limbal cell proliferation, corneal wound healing and regeneration [ 32 , 33 ] and, as expected, the Neurotrophin signaling pathway. The latter was considered for more in-depth analysis: sixty and fifty genes, targeted by 18 and 16 out of 21 miRNAs (miR-337-5p, mir-34a-3p, mir-1227-3p did not show any target gene) were detected by DIANA-TarBase and microT-based analysis, respectively ( Table 4 ).…”

Section: Resultsmentioning

confidence: 99%

MicroRNAs Expression in Response to rhNGF in Epithelial Corneal Cells: Focus on Neurotrophin Signaling Pathway

Compagnoni

Zelli

Bianchi

et al. 2022

IJMS

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Purpose. Nerve growth factor efficacy was demonstrated for corneal lesions treatment, and recombinant human NGF (rhNGF) was approved for neurotrophic keratitis therapy. However, NGF-induced molecular responses in cornea are still largely unknown. We analyzed microRNAs expression in human epithelial corneal cells after time-dependent rhNGF treatment. Methods. Nearly 700 microRNAs were analyzed by qRT-PCR. MicroRNAs showing significant expression differences were examined by DIANA-miRpath v.3.0 to identify target genes and pathways. Immunoblots were performed to preliminarily assess the strength of the in silico results. Results. Twenty-one microRNAs (miR-26a-1-3p, miR-30d-3p, miR-27b-5p, miR-146a-5p, miR-362-5p, mir-550a-5p, mir-34a-3p, mir-1227-3p, mir-27a-5p, mir-222-5p, mir-151a-5p, miR-449a, let7c-5p, miR-337-5p, mir-29b-3p, miR-200b-3p, miR-141-3p, miR-671-3p, miR-324-5p, mir-411-3p, and mir-425-3p) were significantly regulated in response to rhNGF. In silico analysis evidenced interesting target genes and pathways, including that of neurotrophin, when analyzed in depth. Almost 80 unique target genes (e.g., PI3K, AKT, MAPK, KRAS, BRAF, RhoA, Cdc42, Rac1, Bax, Bcl2, FasL) were identified as being among those most involved in neurotrophin signaling and in controlling cell proliferation, growth, and apoptosis. AKT and RhoA immunoblots demonstrated congruence with microRNA expression, providing preliminary validation of in silico data. Conclusions. MicroRNA levels in response to rhNGF were for the first time analyzed in corneal cells. Novel insights about microRNAs, target genes, pathways modulation, and possible biological responses were provided. Importantly, given the putative role of microRNAs as biomarkers or therapeutic targets, our results make available data which might be potentially exploitable for clinical applications.

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The common YAP activation mediates corneal epithelial regeneration and repair with different-sized wounds

Cited by 14 publications

References 46 publications

Unilateral zebrafish corneal injury induces bilateral cell plasticity supporting wound closure

Unilateral zebrafish corneal injury induces bilateral cell plasticity supporting wound closure

Corneal epithelial differentiation of human pluripotent stem cells generates ABCB5+ and ∆Np63α+ cells with limbal cell characteristics and high wound healing capacity

MicroRNAs Expression in Response to rhNGF in Epithelial Corneal Cells: Focus on Neurotrophin Signaling Pathway

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