Abstract
The corneal endothelium (CE) dysfunction impairs optical transparency and leads to corneal allograft failure. Morphologically, CE cells are characterized by premature senescence at the late stage of corneal graft. However, the detailed molecular mechanisms are largely unknown. Here we found that transforming growth factor-β (TGF-β) is elevated in the CE of late graft failure. In addition, senescence-associated gene p21 and p16 are increased as well, which is consistent with their elevation upon TGF-β treatment in human corneal endothelial cell B4G12. Furthermore, TGF-β treatment leads to high positive ratio of SA-β-gal, indicating B4G12 cells undergo cellular senescence. Mechanistically, we demonstrated that TGF-β could induce mitochondrial ROS (mtROS) production and mtROS scavenger could rescue CE cell senescence upon TGF-β treatment. Our study provides new evidence that elevated TGF-β plays a crucial role in the CE cell senescence and loss in chronic corneal graft failure, which could be potential targets for clinical treatment.
Highlights
The acute corneal allograft rejection has been improved significantly over the last two decades, with an overall survival rate could reach 90% at first year
Our results showed that senescence-related genes p16 and p21 were dramatically increased at transcription level or protein level (Fig.1B, D, E), suggesting that decreased corneal endothelial cells may result from increased cellular senescence in the corneal endothelium (CE) with corneal graft failure
We found that TGF-β1 expression was largely elevated at the transcriptional level (Fig.1C) and protein level (Fig. 1D, E) in senescent CE compared to control
Summary
The acute corneal allograft rejection has been improved significantly over the last two decades, with an overall survival rate could reach 90% at first year. It drops to 74% in 5 years and only half sustain success within 10 years [1, 2]. Functional CE cells are essential to keep corneal graft transparency and long-term survival, while CE cell loss can cause corneal opacity overtime after PKP, which is substantial at 5 years post keratoplasty [4] It remains poorly understood how the accelerated www.aging-us.com postoperative loss of CE cells occurs in chronic graft failure. It has fueled the desire to investigate the mechanisms responsible for chronic corneal allograft failure and develop clinically relevant protocols to prevent it
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