Abstract
Reactive gliosis involving activation and proliferation of astrocytes and microglia, is a widespread but largely complex and graded glial response to brain injury. Astroglial population has a previously underestimated high heterogeneity with cells differing in their morphology, gene expression profile, and response to injury. Here, we identified a subset of reactive astrocytes isolated from brain focal ischemic lesions that show several atypical characteristics. Ischemia-derived astrocytes (IDAs) were isolated from early ischemic penumbra and core. IDA did not originate from myeloid precursors, but rather from pre-existing local progenitors. Isolated IDA markedly differ from primary astrocytes, as they proliferate in vitro with high cell division rate, show increased migratory ability, have reduced replicative senescence and grow in the presence of macrophages within the limits imposed by the glial scar. Remarkably, IDA produce a conditioned medium that strongly induced activation on quiescent primary astrocytes and potentiated the neuronal death triggered by oxygen-glucose deprivation. When re-implanted into normal rat brains, eGFP-IDA migrated around the injection site and induced focal reactive gliosis. Inhibition of gamma secretases or culture on quiescent primary astrocytes monolayers facilitated IDA differentiation to astrocytes. We propose that IDA represent an undifferentiated, pro-inflammatory, highly replicative and migratory astroglial subtype emerging from the ischemic microenvironment that may contribute to the expansion of reactive gliosis.Main Points:Ischemia-derived astrocytes (IDA) were isolated from brain ischemic tissueIDA show reduced replicative senescence, increased cell division and spontaneous migrationIDA potentiate death of oxygen-glucose deprived cortical neuronsIDA propagate reactive gliosis on quiescent astrocytes in vitro and in vivoInhibition of gamma secretases facilitates IDA differentiation to astrocytes
Highlights
Reactive gliosis is a widespread, largely complex phenomenon and its biological role in the induction of neuronal survival or death is still under debate
Our results show that ischemia-derived astrocytes (IDAs) obtained from early ischemic lesions exhibit atypical phenotypic features, including low replicative senescence, increased cell division and migratory rates, with the potential to induce reactive gliosis on quiescent astrocytes and neurodegeneration on oxygen-glucose deprived neurons
High magnification confocal images show the extreme changes in the phenotype of penumbral glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes from 1 to 14 days post-lesion (DPL) (Figure 1B)
Summary
Reactive gliosis is a widespread, largely complex phenomenon and its biological role in the induction of neuronal survival or death is still under debate. This is not an on/off mechanism, but rather a graded process from a quiescent state where astrocytes have individual territorial domains to a hypertrophied state with overlapping domains and loss of tissue architecture, leading to the formation of the glial scar (Burda and Sofroniew, 2014). The ischemic penumbra surrounding the core is a region where the blood supply was not completely restricted It remains electrically silent; neurons from this region will die during the 3–5 days. Astrocyte scar formation is essentially complete 2–4 weeks after acute insults (Burda and Sofroniew, 2014)
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