Exosomes derived from human umbilical cord mesenchymal stem cells attenuate neuroinflammation in intracerebral hemorrhage rats by modulating lactylation modification.

Abstract

BACKGROUND: Neuroinflammation following intracerebral hemorrhage (ICH) is a critical contributor to secondary brain injury. Lactylation modification, a novel epigenetic regulatory mechanism, may participate in pathological processes by modulating inflammatory gene expression. This study investigates whether exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSC-exos) alleviate ICH-induced neuroinflammation by regulating lactylation modification via the PI3K/AKT/PKM2/H3K18la axis. METHODS: In vivo, an ICH model was established by stereotactic injection of collagenase IV into the rat striatum. At 6 h post-ICH, hUCMSC-exos (100 μg/200 μL) were administered via tail vein. In vitro, a hemin-induced (20 μM) ICH cell model was established using primary astrocytes, followed by hUCMSC-exos treatment (20 μg/mL) at 6 h post-modeling. The expression of the PI3K/AKT/PKM2/H3K18la axis and inflammatory cytokines (TNF-α, IL-1β, and IL-10) was evaluated in both models to assess the impact of hUCMSC-exos on glycolysis, lactylation modification, and neuroinflammation. Neurological function in ICH rats was evaluated using corner turn, forelimb placement, Longa, and Bederson scores at days 1, 3, 7, and 14. RESULTS: hUCMSC-exos intervention significantly upregulated phosphorylated PI3K (p-PI3K) and AKT (p-AKT) levels, while downregulating PKM2, LDHA, and H3K18la expression. Pro-inflammatory cytokines (TNF-α and IL-1β) were markedly reduced, whereas the anti-inflammatory cytokine IL-10 was elevated. Consequently, hUCMSC-exos improved neurological recovery in ICH rats. CONCLUSION: hUCMSC-exos attenuate ICH-induced glycolysis, lactylation modification, and excessive neuroinflammation via the PI3K/AKT/PKM2/H3K18la axis, offering a novel therapeutic strategy for ICH.