Role of Jagged1-mediated Notch Signaling Activation in the Differentiation and Stratification of the Human Limbal Epithelium

Abstract

The Notch signaling pathway plays a key role in proliferation and differentiation. We investigated the effect of Jagged 1 (Jag1)-mediated Notch signaling activation in the human limbal stem/progenitor cell (LSC) population and the stratification of the limbal epithelium in vitro. After Notch signaling activation, there was a reduction in the amount of the stem/progenitor cell population, epithelial stratification, and expression of proliferation markers. There was also an increase of the corneal epithelial differentiation. In the presence of Jag1, asymmetric divisions were decreased, and the expression pattern of the polarity protein Par3, normally present at the apical-lateral membrane of basal cells, was dispersed in the cells. We propose a mechanism in which Notch activation by Jag1 decreases p63 expression at the basal layer, which in turn reduces stratification by decreasing the number of asymmetric divisions and increases differentiation.

The foggy world(s) of p63 isoform regulation in normal cells and cancer

“…ΔNp63 regulates stem/progenitor cell activities in epithelial tissues and is lost during differentiation of stratifying epithelium (skin, bronchus, etc) or during luminal differentiation (breast, prostate, urothelium). One major keratinocyte differentiation pathway is Notch, and ΔNp63 is suppressed by Notch1 activation [74,115]. Within this pathway, Notch1 ligands Delta‐1 and Jagged 1 downregulated and Notch signalling inhibition increased ΔNp63 [116], whilst ΔNp63 represses NOTCH1 transcription to provide negative feedback regulation [117] (Figure 4A).…”

Limbal stem cell therapy

“…Molecular regulation of LSCs is another approach to supplement soluble factors that sustain the self-renewal of LSCs both in vitro and in vivo. Several signaling pathways such as Wnt, Notch, BMP, Shh, YAP, and TGFb play critical roles in the maintenance and differentiation of LSCs [40][41][42][43][44]. Activation of Wnt signaling and modulation of Notch signaling are shown to impact the LSC proliferation and differentiation in culture, which opens a new approach in enhancing LSC expansion efficiency and survival of LSCs upon chemical injury in culture [45].…”

Therapeutic Strategies for Restoring Perturbed Corneal Epithelial Homeostasis in Limbal Stem Cell Deficiency: Current Trends and Future Directions

“…As the percentage of LSCs is a core determinant of cultivated LSC transplantation success, understanding how modulation of these signaling pathways can promote LSC self-renewal is necessary [ 21 ]. Gonzalez et al [ 101 ] explored the role of Jagged 1 (Jag1)-Notch signaling in human limbal tissue and demonstrated that activation of Notch signaling through a recombinant Jag1 ligand decreases LSC stemness and causes differentiation towards mature corneal epithelium. These results suggest that Jag1-Notch signaling is a negative regulator of LSC stemness, and further research exploring the impact of downregulated Jag1 expression on LSC stemness might identify another strategy for promoting LSC expansion.…”