Clin Transl Med. 2026 Nov;16(11):e70870. doi: 10.1002/ctm2.70870.
ABSTRACT
BACKGROUND: Ischaemic stroke occurs when blood flow to the brain is obstructed. Rapid restoration of blood supply frequently induces cerebral ischaemia‒reperfusion injury (CIRI). Bone marrow mesenchymal stem cell (BMSC)-derived exosomes exhibit promising therapeutic potential for CIRI. In-depth exploration of their therapeutic mechanisms holds crucial significance for CIRI management.
METHODS: The middle cerebral artery occlusion/reperfusion (MCAO) model was established in mice. An in vitro ischaemic stroke model was established by treating BV-2 cells with oxygen‒glucose deprivation/reoxygenation (OGD/R). Exosomes were isolated from BMSCs and intranasally administrated into mice or added into BV-2 cells. Neurological deficits, grasping and coordination function were evaluated. Cell viability, apoptosis, proliferation and migration were examined. The localisation of KLF3-AS1 was examined by combined staining of immunofluorescence and fluorescence in situ hybridisation. Intracellular Ca2+ and adenosine triphosphate levels, mitochondrial reactive oxygen species and membrane potential were assessed.
RESULTS: KLF3-AS1 enhanced BMSC viability, proliferation and migration, accompanied by epigenetic reprogramming at its promoter characterised by increased H3K27 acetylation (H3K27Ac) and decreased H3K27 trimethylation (H3K27Me3). BMSC-derived KLF3-AS1-enriched exosomes indicated therapeutic efficacy in both in vivo and in vitro models of cerebral ischaemia. In MCAO-induced mice, these exosomes alleviated neurological deficits and shifted microglial polarisation from pro-inflammatory M1-like to anti-inflammatory M2-like phenotypes. Similar effects were observed in OGD/R-treated BV-2 microglia, where KLF3-AS1-enriched exosomes attenuated oxidative stress and mitochondrial dysfunction while upregulating Silent Information Regulator 3 (SIRT3) expression. Mechanistically, KLF3-AS1 facilitated ETS Variant Transcription Factor 4 (ETV4) nuclear translocation to activate SIRT3 transcription in microglia, and inhibition of SIRT3 abolished the neuroprotective effects of exosomal KLF3-AS1.
CONCLUSION: BMSC-derived exosomes delivering KLF3-AS1 ameliorates CIRI by preserving microglial mitochondrial function and inhibiting inflammatory polarisation, highlighting KLF3-AS1 as a critical epigenetic regulator and exosome-mediated therapeutic agent for CIRI through the ETV4/SIRT3 axis.
KEY POINTS/HIGHLIGHTS: KLF3-AS1 enhances bone marrow mesenchymal stem cell (BMSC) function via promoter H3K27Ac/H3K27Me3 reprogramming. KLF3‑AS1 directly binds ETS Variant Transcription Factor 4 (ETV4) to activate Silent Information Regulator 3 (SIRT3), preserving mitochondrial integrity. BMSC‑derived exosomal KLF3‑AS1 promotes M2 microglial polarisation and ameliorates cerebral ischaemia-reperfusion injury.
PMID:42965486 | DOI:10.1002/ctm2.70870