DPSCs-Exos promote OPCs differentiation and white matter repair via Myl9-mediated PRMT5 nucleation after ischemic stroke

Abstract

Ischemic stroke often leads to white matter damage due to impaired oligodendrocyte precursor cells (OPCs) differentiation, hindering post-stroke recovery. While dental pulp stem cells-derived exosomes (DPSCs-Exos) have shown promise in stroke recovery, the underlying mechanisms remain unclear. Toward this aim, we investigated the therapeutic potential of DPSCs-Exos for promoting OPCs differentiation and white matter repair after ischemic stroke using in vivo (middle cerebral artery occlusion, MCAO) and in vitro (oxygen-glucose deprivation/reoxygenation, OGD/R) models. Intracerebroventricular DPSCs-Exos were administered on days 1, 3, and 5 post-MCAO, with functional (sensory-motor and cognitive), morphological, and biochemical assessments performed at 7, 14, and 28 days. Our results demonstrated that DPSC-Exos treatment significantly improved functional outcomes, promoted OPCs proliferation and differentiation, and facilitated white matter repair. Mechanistically, DPSC-Exos-mediated OPCs differentiation involves protein arginine methyltransferase 5 (PRMT5) and inhibitor of differentiation 2 (ID2). Specifically, exosomal myosin regulatory light polypeptide 9 (Myl9) interacts with PRMT5 in OPCs, driving PRMT5 nucleation, subsequent CpG island methylation, and ID2 downregulation, ultimately leading to OPCs differentiation into oligodendrocytes (OLs). These findings identify a novel mechanism by which DPSC-Exos promote white matter repair and suggest their potential as a therapeutic strategy for ischemic stroke.