EphA4 regulates white matter remyelination after ischemic stroke through Ephexin‐1/RhoA/ROCK signaling pathway

Abstract

Ischemic stroke, which accounts for nearly 80% of all strokes, leads to white matter injury and neurobehavioral dysfunction, but relevant therapies to inhibit demyelination or promote remyelination after white matter injury are still unavailable. In this study, the middle cerebral artery occlusion/reperfusion (MCAO/R) in vivo and oxygen–glucose deprivation/reoxygenation (OGD/R) in vitro were used to establish the ischemic models. We found that Eph receptor A4 (EphA4) had no effect on the apoptosis of oligodendrocytes using TUNEL staining. In contrast, EphA4 promoted proliferation of oligodendrocyte precursor cells (OPCs), but reduced the numbers of mature oligodendrocytes and the levels of myelin‐associated proteins (MAG, MOG, and MBP) in the process of remyelination in ischemic models in vivo and in vitro as determined using PDGFRα‐EphA4‐shRNA and LV‐EphA4 treatments. Notably, conditional knockout of EphA4 in OPCs (EphA4fl/fl + AAV‐PDGFRα‐Cre) improved the levels of myelin‐associated proteins and functional recovery following ischemic stroke. In addition, regulation of remyelination by EphA4 was mediated by the Ephexin‐1/RhoA/ROCK signaling pathway. Therefore, EphA4 did not affect oligodendrocyte (OL) apoptosis but regulated white matter remyelination after ischemic stroke through the Ephexin‐1/RhoA/ROCK signaling pathway. EphA4 may provide a novel and effective therapeutic target in clinical practice of ischemic stroke.

CD11c+ microglia promote white matter repair after ischemic stroke

“…In addition to EC, white matter of the striatum and cortex in peri-infarcted area also spontaneously repaired from Day 7 after ischemic stroke. In line with our results, studies from Cui et al also reported that remyelination starts from Day 7 after tMCAO by pathological staining [20].…”

Mechanisms of intermittent theta-burst stimulation attenuating nerve injury after ischemic reperfusion in rats through endoplasmic reticulum stress and ferroptosis

“…The number of falls and postural adjustments were observed and scored as the rats walked. The scoring was as follows [ 23 , 24 ]: 0, no ability to stand and fall from the balance beam; 1, no movement but could stay on the balance beam; 2, attempted to walk but would fall and could not pass through the balance beam; 3, walked through the balance beam with more than 50% of the total number of steps with foot slips; 4, walked through the balance beam with less than 50% of the total number of steps with foot slips; 5, successfully passed through the balance beam with only one-foot slip on the affected side; 6, Successfully passed the balance beam without foot slip.…”

Biomaterials targeting the microenvironment for spinal cord injury repair: progression and perspectives

“…Inhibition of myelin formation by Nogo-A has also been associated with activation of OLs and the RhoA-ROCK signaling pathway, and activation of RhoA inhibits differentiation of OPCs to OLs ( Wang et al, 2021 ). Furthermore, cell migration and differentiation are blocked by CSPGs after activation of the RhoA-ROCK pathway in endogenous neural stem cells ( Liu et al, 2022 ), and inhibition of RhoA activation in astrocytes reduces their proliferation and aggregation and extracellular matrix production ( Stern et al, 2021 ).…”