The neuropeptide alpha-melanocyte-stimulating hormone is critical for corneal endothelial cell protection and graft survival after transplantation.

Corneal transplantation is the most common form of tissue transplantation. The success of corneal transplantation mainly relies on the integrity of corneal endothelial cells (CEnCs), which maintain tissue transparency by pumping out excess water from the cornea. After transplantation, the rate of CEnC loss far exceeds that seen with normal aging, and this can threaten sight. The underlying mechanisms are poorly understood. Alpha-melanocyte-stimulating hormone (α-MSH) is a neuropeptide that is constitutively found in the aqueous humor with both cytoprotective and immunomodulatory effects. We found high expression of melanocortin 1 receptor (MC1R), the receptor for α-MSH, on CEnCs. We then set to determine the effect of α-MSH/MC1R signaling on endothelial function and allograft survival in vitro and in vivo using MC1R signaling-deficient mice (Mc1re/e mice with a nonfunctional MC1R). Herein, we show that in addition to its well-known immunomodulatory effect, α-MSH has cytoprotective effects on CEnCs after corneal transplantation and the loss of MC1R signaling significantly decreases long-term graft survival in vivo. In conclusion, α-MSH/MC1R signaling is critical for CEnC function and graft survival after corneal transplantation.