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Characterization of the Limbal Epithelial Stem Cell Niche

ABSTRACT: Limbal epithelial stem cells (LESCs) reside within the LSC niche (LSCN), located at the annular transition zone between the cornea and conjunctiva. LESCs are important for the long-term maintenance of the corneal epithelium and critical for repopulating the corneal epithelium after injury. We have recently identified that a hyaluronan (HA)-rich extracellular matrix (ECM) exists within the LSCN, and that this HA matrix is necessary for maintaining LESCs in the “stem cell” state. Herein we further characterized the composition of the LSCN, identifying key components of the HA-rich matrix. We identified that the hyaladherins IαI, TSG-6 and versican are highly expressed in the limbus when compared to the cornea. For IαI, Heavy chain 5 (HC5) was found to be the most highly expressed HC in the mouse and human cornea, and associates with HA forming HA/HC5 specific matrices. CD44 is the most likely receptor that mediates the interaction between LESCs and the HA-specific matrix. The LSCN is composed of a rich HA matrix that contains HA/HC5. HA/HC5 complexes could be used as an improved substrate for culturing LESCs during ex vivo expansion for limbal stem cell transplantation.

ORGANISM(S): Mus musculus

PROVIDER: GSE244412 | GEO | 2023/11/08

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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Characterization of the Limbal Epithelial Stem Cell Niche

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