Neurology eJournal. 2023 Mar 21
Liang Xu, Qing-Song Wang, Jian-Cheng Liao, Jia-Jun Zheng, Bing Qin, Wen Li, Jia-Xuan Zhang, Wei Li, Xiang-Yu Wang, Mao-Ying Zhang, Gong Chen
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Research Field: CNS

Keywords: human brain, Astrocyte, cell conversion, neural regeneration, in vivo reprogramming

AAV Serotype: AAV9

Targeted organ:human brain slices

Abstract

Transcription factor-mediated cell conversion has been reported in the central nervous system (CNS) of both rodents and non-human primates (NHPs). In particular, astrocyte-to-neuron (AtN) conversion has been achieved in the brain and spinal cord of animal models of neurological disorders for neural regeneration and repair. However, whether AtN conversion can be ultimately used for human brain repair in patients is still unknown. To investigate the applicability of AtN conversion technology in human brain, we established a long-term ex vivo culture system using human brain tissue that is surgically removed from epileptic patients to directly test AtN conversion in human astrocytes. We demonstrate that both neural transcription factors NeuroD1 and Ascl1 can convert human astrocytes into neurons. Importantly, both immunostaining and electrophysiological recordings revealed that the astrocyte-converted neurons showed immature properties during initial 1-2 weeks of conversion, and then acquired more mature properties after 3-4 weeks of conversion. These studies in ex vivo human brain tissue pave a stepping stone toward future clinical trials using transcription factor-based AtN conversion approach to treat neurological disorders.

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