SOX2 Regulates P63 and Stem/Progenitor Cell State in the Corneal Epithelium

• Published in: Stem cells (Dayton, Ohio) Ohio), 2019-03, Vol.37 (3), p.417-429
• Main Authors: Bhattacharya, Swarnabh, Serror, Laura, Nir, Eshkar, Dhiraj, Dalbir, Altshuler, Anna, Khreish, Maroun, Tiosano, Beatrice, Hasson, Peleg, Panman, Lia, Luxenburg, Chen, Aberdam, Daniel, Shalom‐Feuerstein, Ruby
• Format: Article
• Language: English
• Subjects: Abnormalities; Alkaloids; Animals; Blindness; Cell Differentiation; Cell Proliferation; Cells (biology); Cornea; Differentiation; Differentiation (biology); Ectoderm; Epithelium; Epithelium, Corneal - metabolism; Kinases; Limbal epithelial cells; Limbal stem cell; Mice; MicroRNA; Mutation; NIH 3T3 Cells; Phenotypes; Piperidines; Progenitor cells; Regeneration; Signal Transduction; SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism; Stem cell transplantation; Stem cells; Stem Cells - metabolism; Tissue‐Specific Stem Cells; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Vascularization
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.2959

Mutations in key transcription factors SOX2 and P63 were linked with developmental defects and postnatal abnormalities such as corneal opacification, neovascularization, and blindness. The latter phenotypes suggest that SOX2 and P63 may be involved in corneal epithelial regeneration. Although P63 has been shown to be a key regulator of limbal stem cells, the expression pattern and function of SOX2 in the adult cornea remained unclear. Here, we show that SOX2 regulates P63 to control corneal epithelial stem/progenitor cell function. SOX2 and P63 were co‐expressed in the stem/progenitor cell compartments of the murine cornea in vivo and in undifferentiated human limbal epithelial stem/progenitor cells in vitro. In line, a new consensus site that allows SOX2‐mediated regulation of P63 enhancer was identified while repression of SOX2 reduced P63 expression, suggesting that SOX2 is upstream to P63. Importantly, knockdown of SOX2 significantly attenuated cell proliferation, long‐term colony‐forming potential of stem/progenitor cells, and induced robust cell differentiation. However, this effect was reverted by forced expression of P63, suggesting that SOX2 acts, at least in part, through P63. Finally, miR‐450b was identified as a direct repressor of SOX2 that was required for SOX2/P63 downregulation and cell differentiation. Altogether, we propose that SOX2/P63 pathway is an essential regulator of corneal stem/progenitor cells while mutations in SOX2 or P63 may disrupt epithelial regeneration, leading to loss of corneal transparency and blindness. Stem Cells 2019;37:417–429 A working model for the role of SOX2 in the corneal epithelium: SOX2 is essential for corneal stem/progenitor cell function. It controls P63 expression levels to promote cell proliferation and stemness, whereas its downregulation by miR‐450b induces a decrease in P63 and augments cell differentiation.