Tgf Alpha Preserves Oligodendrocyte Lineage Cells And Improves White Matter Integrity After Cerebral Ischemia

Transforming growth factor alpha (TGF-alpha) has been reported to play important roles in neurogenesis and angiogenesis in the injured brain. The present study characterizes a novel role for TGF alpha in oligodendrocyte lineage cell survival and white matter integrity after ischemic stroke. Three days after transient (60 min) middle cerebral artery occlusion (tMCAO), TGF alpha expression was significantly increased in microglia/macrophages and neurons. Expression of the receptor of TGF alpha-epidermal growth factor receptor (EGFR)-was increased in glial cells after ischemia, including in oligodendrocyte lineage cells. TGF alpha knockout enlarged brain infarct volumes and exacerbated cell death in oligodendrocyte precursor cells (OPCs) and oligodendrocytes three days after tMCAO. TGF alpha-deficient mice displayed long-term exacerbation of sensorimotor deficits after tMCAO, and these functional impairments were accompanied by loss of white matter integrity and impaired oligodendrocyte replacement. In vitro studies confirmed that 5 or 10 ng/mL TGF alpha directly protected OPCs and oligodendrocytes against oxygen and glucose deprivation (OGD)-induced cell death, but exerted no effects on OPC differentiation. Further studies identified STAT3 as a key transcription factor mediating the effects of TGF alpha on OPCs and oligodendrocytes. In conclusion, TGF alpha provides potent oligodendrocyte protection against cerebral ischemia, thereby maintaining white matter integrity and improving neurological recovery after stroke.