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 <i>Postn</i> 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 (<i>Hk2</i>) in myeloid cells led to reduced H4K8la and POSTN levels and inhibited RNV. Exogenous exosomal POSTN partially reversed the angiogenic defects caused by <i>Postn</i> or <i>Hk2</i> 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.