Origin and progeny of reactive gliosis: A source of multipotent cells in the injured brain

TLDR

Reactive gliosis is the universal response to brain injury, yet the origin and fate of the reacting glial cells, particularly astrocytes that upregulate GFAP, remain unclear. The study aims to determine whether the proliferating GFAP⁺ cells that appear after injury arise from endogenous glial progenitors or from mature astrocytes that begin to divide. Fate‑mapping and viral targeting revealed that quiescent astrocytes become proliferative after stab‑wound injury, remain lineage‑restricted in vivo, but display multipotency and self‑renewal in vitro, whereas NG2/PDGFRα progenitors do not form neurospheres, indicating that astrocytes acquire stem‑cell‑like properties post‑injury and could aid brain repair.

Abstract

Reactive gliosis is the universal reaction to brain injury, but the precise origin and subsequent fate of the glial cells reacting to injury are unknown. Astrocytes react to injury by hypertrophy and up-regulation of the glial-fibrillary acidic protein (GFAP). Whereas mature astrocytes do not normally divide, a subpopulation of the reactive GFAP(+) cells does so, prompting the question of whether the proliferating GFAP(+) cells arise from endogenous glial progenitors or from mature astrocytes that start to proliferate in response to brain injury. Here we show by genetic fate mapping and cell type-specific viral targeting that quiescent astrocytes start to proliferate after stab wound injury and contribute to the reactive gliosis and proliferating GFAP(+) cells. These proliferating astrocytes remain within their lineage in vivo, while a more favorable environment in vitro revealed their multipotency and capacity for self-renewal. Conversely, progenitors present in the adult mouse cerebral cortex labeled by NG2 or the receptor for the platelet-derived growth factor (PDGFRalpha) did not form neurospheres after (or before) brain injury. Taken together, the first fate-mapping analysis of astrocytes in the adult mouse cerebral cortex shows that some astrocytes acquire stem cell properties after injury and hence may provide a promising cell type to initiate repair after brain injury.