Signaling Pathways Impact on Induction of Corneal Epithelial-like Cells Derived from Human Wharton’s Jelly Mesenchymal Stem Cells

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.

Resveratrol’s Impact on the Chondrogenic Reagents’ Effects in Cell Sheet Cultures of Wharton’s Jelly-Derived MSCs

“…WJ-MSCs can be isolated from the connective tissue surrounding the umbilical cord vessels, which makes them more primitive than any adult mesenchymal stem/stromal cells (MSCs); at the same time, their use does not cause the ethical problems that the use of fetal tissue does [2]. In addition to the adipogenic, chondrogenic, and osteogenic differentiation standards for MSCs, WJ-MSCs can also differentiate into endothelial cells [3], Schwann cells [4], endometrial cells [5], corneal epithelial cells [6], and other cell types; that is, they are able to transform into cells of other germ layers. Moreover, WJ-MSCs express pluripotency markers such as Nanog, Oct-4, and Ssea-4, although to a lesser extent compared with induced pluripotent stem cells (iPSCs) [7].…”