Efficient Dlx2‐mediated astrocyte‐to‐neuron conversion and inhibition of neuroinflammation by NeuroD1

Abstract In vivo astrocyte‐to‐neuron (AtN) conversion induced by overexpression of neural transcriptional factors has great potential for neural regeneration and repair. Here, we demonstrate that a single neural transcriptional factor, Dlx2, converts mouse striatal astrocytes into neurons in a dose‐dependent manner. Lineage‐tracing studies in Aldh1l1‐CreERT2 mice confirm that Dlx2 can convert striatal astrocytes into DARPP32 + and Ctip2 + medium spiny neurons (MSNs). Time‐course studies reveal a gradual conversion from astrocytes to neurons in 1 month, with a distinct intermediate state in between astrocytes and neurons. Interestingly, when Dlx2‐infected astrocytes start to lose astrocytic markers, the other local astrocytes proliferate to maintain astrocytic levels in the converted areas. Unexpectedly, although Dlx2 efficiently reprograms astrocytes into neurons in the gray matter striatum, it also induces partial reprogramming of astrocytes in the white matter corpus callosum. Such partial reprogramming of white matter astrocytes is associated with neuroinflammation, which can be suppressed by the addition of NeuroD1. Our results highlight the importance of investigating AtN conversion in both the gray matter and white matter to thoroughly evaluate therapeutic potentials. This study also unveils the critical role of anti‐inflammation by NeuroD1 during AtN conversion.