Glial scar formation by reactive astrocytes derived from oligodendrocyte progenitor cells after closed-head injury

Abstract

The diversity of reactive astrocytes is key to understanding complicated pathological processes in the brain. The accumulation of reactive astrocytes expressing the neural stem/precursor cell marker Nestin is common after brain injury, but the pathological implications of this reactive astrocyte subpopulation remain elusive. This study initially aimed to determine the origin and fate of these reactive astrocytes expressing Nestin by characterizing cells labeled with green fluorescent protein (GFP) after closed-head injury, using a Nestin promoter region widely utilized to study neural stem/precursor cells. Unexpectedly, oligodendrocyte progenitor cells (OPCs), rather than astrocytes, were robustly and selectively labeled with GFP. A fraction of these cells showed a subsequent upregulation of astrocyte markers and were incorporated into glial scars. These glial scars are aggregates of reactive astrocytes that form between lesion cores and the perilesional recovering region. Deletion of the Stat3 gene, which is essential for astrocyte activation, using a Nestin promoter reduced glial scars, further confirming that OPCs are involved in glial scar formation. Reactive astrocytes labeled with a glial fibrillary acidic protein promoter differed in morphology and distribution from astrocytes derived from OPCs. This confirms that astrocytes and OPCs produce distinct reactive astrocyte subpopulations. Some GFP-labeled OPCs lacking astrocyte markers were found to distribute in perilesional recovering regions. The reduced expression of Nestin and OPC markers in these non-astrocytic descendants of OPCs, coupled with a significant fraction of these cells remaining olig2-positive, suggests that OPCs give rise to both reactive astrocytes and oligodendrocytes. These findings suggest that OPCs are activated by a novel process after brain injury.