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Human adipose-derived mesenchymal stem cell-derived exosomes induce epithelial remodeling and anti-scar healing revealed by single-cell RNA sequencing

ABSTRACT: Effectively managing skin wounds to achieve quick and scarless healing is a significant clinical challenge. Several cell types participate in wound healing, including keratinocytes, fibroblasts, and many others. Human adipose-derived mesenchymal stem cell-derived exosomes (hADSC-Exos) are regarded as promising therapeutic choice. However, a comprehensive understanding of what mechanisms promote regenerative healing respond to hADSC-Exos treatment is still limited. Here, we utilize a high-resolution single-cell RNA sequencing analysis (scRNA-seq) from adult wild-type mice, postoperative day (POD) 14 mice and hADSC-Exos-treated postoperative day (POD) 14 mice. hADSC-Exos influences epithelial cells and fibroblasts, leading to scar-free wound healing. Among epithelial cell subtypes, Lef1high proliferating keratinocytes (prolif KC) are particularly remodeled by hADSC-Exos. Prolif KC exhibit epithelial-mesenchymal plasticity (EMP). The cell-cell communication between keratinocytes and fibroblasts in anti-scar healing is modulated by TGF-β1, which promote EMP transition cascade. hADSC-Exos may inhibit wound fibrosis through the 14-3-3Zeta-YES-associated protein (YAP)-hippo signaling pathway. This study enhances our understanding of epithelial cell diversity and interactions in wound healing, highlighting hADSC-Exos-induced prolif KC as potential reprogramming targets. These epithelial cells present promising therapeutic targets for improving wound healing strategies.

ORGANISM(S): Mus musculus

PROVIDER: GSE298086 | GEO | 2025/06/03

REPOSITORIES: GEO

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Project description:Limbal stem cells including epithelial and stromal/Mesenchymal stem cells that contribute to sustained corneal homeostasis, maintain their ability to act as self-renewal progenitor cells by virtue of their limbal niche and intercellular communication. Extracellular vehicles (EVs), including exosomes (Exos), are important paracrine mediators through their cargo transfer for intercellular communication in various stem cell niches. Previously we have shown the differential cargos and regulatory roles of limbal stromal cell (LSC)-derived Exos, in limbal epithelial cells (LEC) in normal (N) and diabetic (DM) limbal niche. In the present study, to have a comprehensive knowledge of reciprocal LEC-LSC crosstalk, we investigated the proteomics and miRNA profile of exosomes derived from LEC and their regulatory roles in LSC in N and DM limbus. Our study showed wound healing and proliferation rates in primary N-LSC were significantly enhanced upon treatment by normal LEC-derived Exos (N-Exos), but not by diabetic Exos (DM-Exos). Further, N-Exos treated LSC showed downregulation of keratocyte markers, ALDH3A1 and lumican, but not keratocan, and upregulation of MSC markers, CD105, CD90, and CD73 compared to the DM-Exos treated LSC. Using next generation sequencing (NGS) and proteomics analysis, we revealed some miRNAs and proteins in the Exos that affect the cellular crosstalk and the function of the cornea. We also documented differences in DM vs. normal LEC-derived Exo’s cargos. Overall, DM-Exos have less effect on LSC proliferation, wound healing, and stem cell maintenance than N-Exos, likely by transferring their cargo proteins and/or regulatory miRNAs targeting cell cycle, ERK/MAPK, TGF-β, EMT, PI3K-Akt-mTOR signaling molecules. This suggests that the small RNA and protein cargo differences in DM vs. N LEC-derived Exos could contribute to the disease state. Our study revealed a complex contribution of Exos to health and diabetic state of corneal homeostasis and suggests the potential of EV therapeutics for diabetic cornea regenerative medicine

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Human adipose-derived mesenchymal stem cell-derived exosomes induce epithelial remodeling and anti-scar healing revealed by single-cell RNA sequencing

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