Stab Wound Injury Elicits Transit Amplifying Progenitor-like Phenotype in Parenchymal Astrocytes

Abstract

Astrocytes exhibit dual roles in central nervous system (CNS) recovery, offering both beneficial and detrimental effects. Following CNS injury, a subset of astrocytes undergoes proliferation, de-differentiation, and acquires self-renewal and neurosphere-forming capabilities in vitro. This subset of astrocytes represents a promising target for initiating brain repair processes and holds potential for neural recovery. However, studying these rare plastic astrocytes is challenging due to the absence of distinct markers. In our study, we characterized these astrocytic subpopulations using comparative single-cell transcriptome analysis. By leveraging the regenerative properties observed in radial glia of zebrafish, we identified and characterized injury-induced plastic astrocytes in mice. These injury-induced astrocytic subpopulations were predominantly proliferative and demonstrated the capacity for self-renewal and neurosphere formation, ultimately differentiating exclusively into astrocytes. Integration with scRNAseq data of the subependymal zone (SEZ) allowed us to trace the origins of these injury-induced plastic astrocytic subpopulations to parenchymal astrocytes. Our analysis revealed that a subset of these injury-induced astrocytes shares transcriptional similarities with endogenous transient amplifying progenitors (TAPs) within the SEZ, rather than with neural stem cells (NSCs). Notably, these injury-induced TAP-like cells exhibit distinct differentiation trajectories, favoring gliogenic over neurogenic differentiation. In summary, our study identifies a rare subset of injury-induced, proliferative plastic astrocytes with neurosphere-forming capacities. These cells originate from reactive astrocytes and resemble TAPs in their transcriptional profile. This study enhances our understanding of astrocyte plasticity post-injury. HighlightsO_LISingle-cell transcriptomics and cross-species comparisons reveal proliferative and de-differentiated plastic astrocytes following CNS injury. C_LIO_LIInjury-induced de-differentiated astrocytes exhibit remarkable in vitro self-renewal and neurosphere formation but favor glial differentiation. C_LIO_LIDe-differentiated astrocytes exhibit transcriptional similarities to transit-amplifying progenitors (TAPs) over neural stem cells (NSCs) C_LIO_LIInjury-induced TAP-like progenitors exhibit limited spontaneous neuronal differentiation. C_LI