Single‐Cell RNA Sequencing Uncovers Molecular Features Underlying the Disrupted Neurogenesis Following Traumatic Brain Injury

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, with limited effective treatment strategies. Endogenous neural stem cells (NSCs) give rise to neurons and glial cells throughout life. However, NSCs are more likely to differentiate into glial cells rather than neurons at the lesion site after TBI and the underlying molecular mechanism remains largely unknown. Here, we performed large-scale single-cell transcriptome sequencing of subventricular zone (SVZ) NSCs and NSCs-derived cells in the mouse brain, and provide molecular evidence for previous observations that glial differentiation of NSCs prevails after TBI. In addition, we show that the disrupted neurogenesis following TBI is caused by the reduction of a NSC subcluster (NSC-4) expressing the neuronal gene Tubb3. Finally, we demonstrate that the transcriptional factor Dlx2 is significantly downregulated in NSC-4, and Dlx2 overexpression is sufficient to drive NSCs towards neuronal lineage differentiation at the expense of astrocytic lineage differentiation under pro-inflammatory conditions.