Monocyte-derived exosomal periostin driven by histone lactylation contributes to retinal neovascularization
Abstract
Exosomes are signaling messengers facilitating intercellular communication by delivering molecular cargo. Here, we observed increased levels of exosomal periostin (POSTN) in the blood plasma of patients with proliferative diabetic retinopathy (PDR). Monocytes contributed to elevated levels of exosomal POSTN, and deletion of Postn in myeloid cells reduced retinal neovascularization (RNV). Monocytes isolated from the blood of PDR patients or under high glucose conditions exhibited heightened glycolytic activity and elevated histone lactylation levels, particularly H4K8 lactylation (H4K8la). Knockout of hexokinase 2 ( Hk2 ) in myeloid cells led to reduced H4K8la and POSTN levels and inhibited RNV. Exogenous exosomal POSTN partially reversed the angiogenic defects caused by Postn or Hk2 deletion in myeloid cells. Mechanistically, exosomal POSTN stabilized hypoxia-inducible factor -1 alpha and upregulated the expression of angiogenic genes. Notably, treatment with metformin reduced RNV by decreasing monocyte glycolysis and lowering exosomal POSTN levels. In summary, these findings underscore the critical role of circulating exosomal POSTN in RNV and highlight its potential as a therapeutic target for angiogenic retinopathies.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (20)
Wei Shen
Zheng Nie
Department of Ophthalmology, Shanghai Changhai Hospital, Naval Medical University
Mengzhu Wang
Department of Ophthalmology, Shanghai Changhai Hospital, Naval Medical University
Haorui Zhang
Department of Ophthalmology, Shanghai Changhai Hospital, Naval Medical University
Yongxuan Liu
Department of Ophthalmology, Shanghai Changhai Hospital, Naval Medical University
Huimin Zhu
Department of Ophthalmology, Shanghai Changhai Hospital, Naval Medical University
Wen Zhou
Lin Zhang
Min Zhao
Hao Zeng
Department of Ophthalmology, Shanghai Changhai Hospital, Naval Medical University
Mai Peng
Department of Ophthalmology, Shanghai Changhai Hospital, Naval Medical University
Yukun Zhou
Department of Ophthalmology, Shanghai Changhai Hospital, Naval Medical University
Jiawei Zhao
State Key Laboratory of Physical Chemistry of Solid Surfaces, iChEM, College of Chemistry and Chemical Engineering, Innovation Laboratory for Sciences and Technologies of Energy Materials of Fujian Province (IKKEM), Xiamen University, Xiamen 361005, China
Shikun Wang
Department of Ophthalmology, Shanghai Changhai Hospital, Naval Medical University
Guangping Gao
Yuxin Jiang
Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Wenbin Zou
Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Shanghai Changhai Hospital, Naval Medical University
Xi Shen
Beijing National Laboratory for Condensed Matter Physics, Institute of Physics
Liqiang Wang
Department of Mechanical Engineering
Hongyuan Song
Department of Ophthalmology, Shanghai Changhai Hospital, Naval Medical University