TGFα preserves oligodendrocyte lineage cells and improves white matter integrity after cerebral ischemia.

Abstract

Transforming growth factor α (TGF-α) has been reported to play important roles in neurogenesis and angiogenesis in the injured brain. The present study characterizes a novel role for TGFα in oligodendrocyte lineage cell survival and white matter integrity after ischemic stroke. Three days after transient (60 min) middle cerebral artery occlusion (tMCAO), TGFα expression was significantly increased in microglia/macrophages and neurons. Expression of the receptor of TGFα-epidermal growth factor receptor (EGFR)-was increased in glial cells after ischemia, including in oligodendrocyte lineage cells. TGFα knockout enlarged brain infarct volumes and exacerbated cell death in oligodendrocyte precursor cells (OPCs) and oligodendrocytes three days after tMCAO. TGFα-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 TGFα 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 TGFα on OPCs and oligodendrocytes. In conclusion, TGFα provides potent oligodendrocyte protection against cerebral ischemia, thereby maintaining white matter integrity and improving neurological recovery after stroke.

• Authors: Xuejiao Dai, Jie Chen, Fei Xu, Jingyan Zhao, Wei Cai, Zeyu Sun, T Kevin Hitchens, Lesley M Foley, Rehana K Leak, Jun Chen, Xiaoming Hu
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 40 Issue 3 Pg. 639-655 (03 2020) ISSN: 1559-7016 [Electronic] United States
• PMID: 30834805 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• STAT3 Transcription Factor
• Stat3 protein, mouse
• Transforming Growth Factor alpha

Topics

• Animals
• Brain Infarction (genetics, metabolism, pathology)
• Disease Models, Animal
• Mice
• Mice, Knockout
• Oligodendroglia (metabolism, pathology)
• STAT3 Transcription Factor (genetics, metabolism)
• Transforming Growth Factor alpha (genetics, metabolism)
• White Matter (metabolism, pathology)