Abstract
Corneal epithelium, the outmost layer of the cornea, comprises corneal epithelial cells (CECs) that are continuously renewed by limbal epithelial stem cells (LESCs). Loss or dysfunction of LESCs causes limbal stem cell deficiency (LSCD) which results in corneal epithelial integrity loss and visual impairment. To regenerate the ocular surface, transplantation of stem cell-derived CECs is necessary. Human Wharton’s jelly derived mesenchymal stem cells (WJ-MSCs) are a good candidate for cellular therapies in allogeneic transplantation. This study aimed to test the effects of treatments on three signaling pathways involved in CEC differentiation as well as examine the optimal protocol for inducing corneal epithelial differentiation of human WJ-MSCs. All-trans retinoic acid (RA, 5 or 10 µM) inhibited the Wnt signaling pathway via suppressing the translocation of β-catenin from the cytoplasm into the nucleus. SB505124 downregulated the TGF-β signaling pathway via reducing phosphorylation of Smad2. BMP4 did not increase phosphorylation of Smad1/5/8 that is involved in BMP signaling. The combination of RA, SB505124, BMP4, and EGF for the first 3 days of differentiation followed by supplementing hormonal epidermal medium for an additional 6 days could generate corneal epithelial-like cells that expressed a CEC specific marker CK12. This study reveals that WJ-MSCs have the potential to transdifferentiate into CECs which would be beneficial for further applications in LSCD treatment therapy.
Highlights
Cornea, the anterior transparent part of the eye, permits light transmission to photoreceptor cells in the retina and protects the eye from the external environment
Primary human Wharton’s jelly derived mesenchymal stem cells (WJ-MSCs) were successfully isolated by explant culture
We focused on finding an optimal method to differentiate WJ-MSCs into corneal epithelial cells (CECs) in vitro by comparing three combinations in the first step and differentiation duration (9 or 12 days)
Summary
The anterior transparent part of the eye, permits light transmission to photoreceptor cells in the retina and protects the eye from the external environment. The cornea consists of three cell layers: corneal epithelium, stroma, and endothelium. The corneal epithelium, the outmost layer of the cornea, comprises corneal epithelial cells (CECs) that are continuously renewed by limbal epithelial stem cells (LESCs). LESCs are located at the basal layer of the limbus [1] which is the border between the cornea and the sclera. LESCs can divide asymmetrically to produce both LESC daughters and transit-amplifying cells. While LESCs remain in the limbus, transit-amplifying cells migrate into the central cornea and move upward to the superficial layer of the cornea to differentiate into CECs [2,3]
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