In Vivo Partial Cell Reprogramming With Yamanaka Factors Reduced Ischemic Brain Damage in Aging Mice

ABSTRACT Aging is associated with functional decline and reduced regenerative capacity in the brain, is also the strongest risk factor for ischemic stroke, which remains a leading cause of mortality and long‐term disability worldwide, and is associated with impaired functional recovery. Here, we investigated whether short‐term partial cellular reprogramming through cyclic expression of Yamanaka factors (OSKM) in a Tet‐ON mouse model under Rosa‐26 promoter has any impact on ischemic damage in aged mice. To assess ischemic resilience, mice underwent permanent middle cerebral artery occlusion (pMCAo). Forty‐eight hours after ischemia, OSKM‐induced mice displayed significantly smaller damaged area compared with wild‐type controls, accompanied by improved neurological scores and enhanced performance in the tightrope test, suggesting preserved sensorimotor abilities. Notably, myelin integrity was preserved in OSKM‐treated mice, as shown by Black‐Gold staining and stable MAG and MBP expression, whereas wild‐type mice exhibited pronounced demyelination. Given the role of oligodendrocytes in myelin maintenance, we quantified the abundance of their different populations. OSKM induction significantly increased total oligodendrocytes (Olig2 + ) and oligodendrocyte precursor cells (PDGFRα + ) following ischemia, suggesting an enhanced reparative response. Moreover, partial reprogramming(definition) preserved neuronal density in the ischemic cortex and prevented the marked astrocytic activation observed in wild‐type mice, while microglial responses remained comparable across genotypes. These findings demonstrate that cyclic partial reprogramming in aged mice reduces ischemic damage, highlighting OSKM induction as a promising strategy for enhancing brain resilience during cerebrovascular accidents.