Senolytic Treatment Alleviates Corneal Allograft Rejection Through Upregulation of Angiotensin-Converting Enzyme 2 (ACE2)

Overview

Journal Invest Ophthalmol Vis Sci

Date 2025 Feb 6

PMID 39913165

Authors

Hao Chi

Li Ma

Fanxing Zeng

Xiaolei Wang

Peng Peng

Xiaofei Bai

Ting Zhang

Wenhui Yin

Yaoyao Yu

Lingling Yang

Qingjun Zhou

Chao Wei

Weiyun Shi

Affiliations

Soon will be listed here.

Abstract

Purpose: Allograft rejection remains a major cause of failure in high-risk corneal transplants, but the underlying mechanisms are not fully understood. This study aimed to investigate the contribution of transplantation stress-induced cellular senescence to corneal allograft rejection and to elucidate the associated molecular mechanisms.

Methods: Age-matched murine corneal transplantation models were established. Cellular senescence was evaluated using senescence-associated β-galactosidase (SA-β-Gal) staining, western blot, and immunofluorescence staining. The role of cellular senescence in corneal allograft rejection was analyzed using p16 knockout mice and adoptive transfer experiments. Senolytic treatment with ABT-263 was administered intraperitoneally to evaluate its effects on corneal allograft rejection. RNA sequencing and pharmacological approaches were employed to identify the underlying mechanisms.

Results: Surgical injury induced a senescence-like phenotype in both donor corneas and recipient corneal beds, characterized by an increased accumulation of SA-β-Gal-positive cells in the corneal endothelium and stroma and elevated expression of senescence markers p16 and p21. Using genetic and adoptive transfer models, transplantation stress-induced senescence was shown to exacerbate corneal allograft rejection. Importantly, clearance of senescent cells by ABT-263 significantly suppressed ocular alloresponses and immune rejection. Mechanistically, RNA sequencing and loss-of-function experiments demonstrated that the anti-rejection effects of senolytic treatment were closely dependent on angiotensin-converting enzyme 2 (ACE2).

Conclusions: These findings highlight transplantation stress-induced senescence as a pivotal pathogenic factor in corneal allograft rejection. Senolytic therapy emerges as a potential novel strategy to mitigate transplant rejection and improve corneal allograft survival.

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