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Multi-omics analysis identifies coordination and hierarchy of transcription factors controlling specific epithelial cell fates in corneal epithelium [scRNA-seq]

ABSTRACT: The homeostasis of the transparent corneal epithelium in the eye is maintained by the proliferation and differentiation of limbal stem cells that possess the proper cell fate. A potential disease mechanism underlying corneal opacity has been proposed to be limbal stem cells acquiring the cell fate of keratinocytes in the non-transparent epidermis. In this study, we performed a multi-omics analysis of human limbal stem cells derived from the cornea and keratinocytes from the epidermal stratum basale and characterized the similar yet distinct molecular signatures of these cells. By gene regulatory network analysis, we identified cell fate defining transcription factors and their regulatory hierarchy that are shared by the two cell types and those that regulate specific epithelial programs. Our findings indicate that shared transcription factors often regulate limbal stem cell-specific transcription factors. Single-cell RNA-seq analysis of the cornea and the epidermis confirms the shared and specific transcription factor expression patterns in the stem cells of these tissues. Finally, we showed that genes associated with corneal opacity can cooperatively be targeted by the shared and limbal stem cell-specific transcription factors. By characterizing molecular signatures, our study uncovers the distinct regulatory circuitry controlling limbal stem cell fates and corneal opacity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE242995 | GEO | 2023/09/22

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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Multi-omics analysis identifies coordination and hierarchy of transcription factors controlling specific epithelial cell fates in corneal epithelium [scRNA-seq]

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