Neurog2 directly converts astrocytes into functional neurons in midbrain and spinal cord

Fei Liu,Jianhua Xu,Xiaojing Wang,Fuliang Chen,Sue Han,Zhiping Rao,Jiacheng Yuan,Yijie Zhang,Dengyu Lu,Junlan Geng,Yueguang Liu,Sanlan Li,Yuhan Shi,Li Sun

doi:10.1038/s41419-021-03498-x

Abstract

Conversion of astrocytes into neurons in vivo offers an alternative therapeutic approach for neuronal loss after injury or disease. However, not only the efficiency of the conversion of astrocytes into functional neurons by single Neurog2, but also the conundrum that whether Neurog2-induced neuronal cells (Neurog2-iNs) are further functionally integrated into existing matured neural circuits remains unknown. Here, we adopted the AAV(2/8) delivery system to overexpress single factor Neurog2 into astrocytes and found that the majority of astrocytes were successfully converted into neuronal cells in multiple brain regions, including the midbrain and spinal cord. In the midbrain, Neurog2-induced neuronal cells (Neurog2-iNs) exhibit neuronal morphology, mature electrophysiological properties, glutamatergic identity (about 60%), and synapse-like configuration local circuits. In the spinal cord, astrocytes from both the intact and lesioned sources could be converted into functional neurons with ectopic expression of Neurog2 alone. Notably, further evidence from our study also proves that Neurog2-iNs in the intact spinal cord are capable of responding to diverse afferent inputs from dorsal root ganglion (DRG). Together, this study does not merely demonstrate the feasibility of Neurog2 for efficient in vivo reprogramming, it gives an indication for the Neurog2-iNs as a functional and potential factor in cell-replacement therapy.

Highlights

Dysfunction of the central nervous system in traumatic injury and neurodegenerative diseases is associated with neuronal cell loss
Adult neurogenesis primarily occurs in a few specific areas of the brain, such as the subventribular zone (SVZ) lining the lateral ventricles, as well as the subgranular zone within the dendate gyrus (DG) of the hippocampus, whose primary function points to the process of brain plasticity rather than brain repair[1,2]
To test the capability of astrocyte-to-neuron conversion induced by Neurog[2], associated virus (AAV)-mCherry and AAV-Neurog2/ mCherry were injected separately into the adult dorsal midbrain of wild-type (WT) adult mice

Summary

Introduction

Dysfunction of the central nervous system in traumatic injury and neurodegenerative diseases is associated with neuronal cell loss. Several strategies have been employed for the Substantial progress has been made in direct reprogramming of converting glial cells into neurons in vivo[5,6]. From 2013 onwards, numerous studies have discovered that the expression of a single transcription factor (TF), such as NeuroD1 and Ascl[1], is able to directly convert endogenous glial cells into neuroblasts or neurons[8,9,10,11,12,13,14]. Other researchers stated the ability to the neuronal reconstruction of in-vivo-reprogrammed neurons, in particular damaged neural circuit of vision in blind mice and even in a Parkinson’s disease mouse model whose motor behavior was moderately corrected[15,16,17]

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Results

Conclusion