Abstract
To maintain corneal transparency, corneal endothelial cells (CECs) exert a pump function against aqueous inflow. However, human CECs are arrested in the G1-phase and non-proliferative in vivo. Thus, treatment of corneal endothelial decompensation is limited to corneal transplantation, and grafts are vulnerable to immune rejection. Here, we show that ribonuclease (RNase) 5 is more highly expressed in normal human CECs compared to decompensated tissues. Furthermore, RNase 5 up-regulated survival of CECs and accelerated corneal endothelial wound healing in an in vitro wound of human CECs and an in vivo cryo-damaged rabbit model. RNase 5 treatment rapidly induced accumulation of cytoplasmic RNase 5 into the nucleus, and activated PI3-kinase/Akt pathway in human CECs. Moreover, inhibition of nuclear translocation of RNase 5 using neomycin reversed RNase 5-induced Akt activation. As a potential strategy for proliferation enhancement, RNase 5 increased the population of 5-bromo-2′-deoxyuridine (BrdU)-incorporated proliferating CECs with concomitant PI3-kinase/Akt activation, especially in CECs deprived of contact-inhibition. Specifically, RNase 5 suppressed p27 and up-regulated cyclin D1, D3, and E by activating PI3-kinase/Akt in CECs to initiate cell cycle progression. Together, our data indicate that RNase 5 facilitates corneal endothelial wound healing, and identify RNase 5 as a novel target for therapeutic exploitation.
Highlights
Ribonuclease (RNase) 5, commonly known as angiogenin (ANG), is a 14.4-kDa single-chain protein originally identified as a potent inducer of neovascularization[15]
We compared the expression of RNase 5 in human corneal endothelial tissues from deceased subjects without previous cancer or ocular disorders to RNase 5 expression in excised corneal endothelial tissues from patients with corneal endothelial decompensation caused by pseudophakic bullous keratopathy, infection, or burns obtained during keratoplasty
No definite regenerative zone has been ascertained in the human corneal endothelium
Summary
Ribonuclease (RNase) 5, commonly known as angiogenin (ANG), is a 14.4-kDa single-chain protein originally identified as a potent inducer of neovascularization[15]. We hypothesized that human CECs may be physiologically armed with self-protective mechanisms against aging and injury, including surgery, trauma, and the lifelong shear stress of aqueous flow in corneal endothelium generated by rapid eye movements during sleep[38] and convection flow in the anterior chamber. To explore this hypothesis, we investigated the expression of RNase 5, a candidate homeostatic factor, in normal and decompensated human corneal endothelial tissue. Our findings suggest that RNase 5, by virtue of its ability to induce CECs to exit the cell cycle, may be a novel treatment approach for corneal endothelial dysfunction
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