Int J Biol Sci 2019; 15(12):2676-2691. doi:10.7150/ijbs.35630

Research Paper

The PACAP-derived peptide MPAPO facilitates corneal wound healing by promoting corneal epithelial cell proliferation and trigeminal ganglion cell axon regeneration

Zixian Wang1,2, Wailan Shan1,2, Huixian Li1,2, Jia Feng1,2, Shiyin Lu1,2, Biqian Ou1,2, Min Ma3, Yi Ma1,2,✉

1. Institute of Biomedicine, Department of Cellular Biology, Jinan University
2. National engineering research center of genetic Medicine, Key laboratory of Bioengineering Medicine of Guangdong Province, Jinan University
3. College of traditional Chinese Medicine, Jinan University

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Citation:
Wang Z, Shan W, Li H, Feng J, Lu S, Ou B, Ma M, Ma Y. The PACAP-derived peptide MPAPO facilitates corneal wound healing by promoting corneal epithelial cell proliferation and trigeminal ganglion cell axon regeneration. Int J Biol Sci 2019; 15(12):2676-2691. doi:10.7150/ijbs.35630. Available from http://www.ijbs.com/v15p2676.htm

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Abstract

It is well known that the cornea plays an important role in providing protection to the eye, but it is fragile and vulnerable. To clarify the biological effects and molecular mechanisms of the pituitary adenylate cyclase activating polypeptide (PACAP)-derived peptide MPAPO (named MPAPO) to promote corneal wound healing, we applied a mechanical method to establish a corneal injury model and analyzed the repair effects of MPAPO on corneal injury. MPAPO significantly promoted corneal wound repair in C57BL/6 mice. In addition, we established injury models of epithelial cells and trigeminal ganglion cells with H2O2. The results show that when the concentration of MPAPO is 1 μM, it can significantly promote the repair of injured corneal epithelial cells and the regeneration of trigeminal ganglion cell axons. MPAPO repairs epithelial cells through the promotion of GSK3β phosphorylation by binding to PAC1 and activating AKT. β-catenin escapes the phosphorylation of GSK3β and enters the nucleus to promote the expression of cyclin D1, accelerate cell cycle progression and promote cell proliferation. MPAPO promotes axonal regeneration by binding to the PAC1 receptor and activating adenylate cyclase activity, followed by the cAMP activation of protein kinase A activity and the promotion of CREB phosphorylation. Phosphorylated CREB promotes Bcl2 expression and axonal regeneration. In conclusion, our data support the role of MPAPO to facilitate corneal wound healing by promoting corneal epithelial cell proliferation and trigeminal ganglion cell axon regeneration.

Keywords: PAC1 receptor, corneal wound healing, pituitary adenylate cyclase-activating polypeptide (PACAP), corneal epithelial cells, Wnt/β-catenin signaling pathway