{"doi":"10.3389/fcell.2020.591883","title":"Regeneration of Functional Neurons After Spinal Cord Injury via in situ NeuroD1-Mediated Astrocyte-to-Neuron Conversion","abstract":"Spinal cord injury (SCI) often leads to impaired motor and sensory functions, partially because the injury-induced neuronal loss cannot be easily replenished through endogenous mechanisms. In vivo neuronal reprogramming has emerged as a novel technology to regenerate neurons from endogenous glial cells by forced expression of neurogenic transcription factors. We have previously demonstrated successful astrocyte-to-neuron conversion in mouse brains with injury or Alzheimer's disease by overexpressing a single neural transcription factor NeuroD1. Here we demonstrate regeneration of spinal cord neurons from reactive astrocytes after SCI through AAV NeuroD1-based gene therapy. We find that NeuroD1 converts reactive astrocytes into neurons in the dorsal horn of stab-injured spinal cord with high efficiency (~95%). Interestingly, NeuroD1-converted neurons in the dorsal horn mostly acquire glutamatergic neuronal subtype, expressing spinal cord-specific markers such as Tlx3 but not brain-specific markers such as Tbr1, suggesting that the astrocytic lineage and local microenvironment affect the cell fate after conversion. Electrophysiological recordings show that the NeuroD1-converted neurons can functionally mature and integrate into local spinal cord circuitry by displaying repetitive action potentials and spontaneous synaptic responses. We further show that NeuroD1-mediated neuronal conversion can occur in the contusive SCI model with a long delay after injury, allowing future studies to further evaluate this in vivo reprogramming technology for functional recovery after SCI. In conclusion, this study may suggest a paradigm shift from classical axonal regeneration to neuronal regeneration for spinal cord repair, using in vivo astrocyte-to-neuron conversion technology to regenerate functional new neurons in the gray matter.","journal":"Frontiers in Cell and Developmental Biology","year":2020,"id":53016,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":124,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9457,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":269930,"name":"Yan Ding","orcid":"0000-0003-3119-9529","position":1,"is_corresponding":false},{"id":269931,"name":"Fengyu Zhang","orcid":"0000-0001-8504-0770","position":2,"is_corresponding":false},{"id":269932,"name":"Mengjie Pan","orcid":"0009-0000-0796-1515","position":3,"is_corresponding":false},{"id":269933,"name":"Zhuofan Lei","orcid":"0000-0002-4207-2796","position":4,"is_corresponding":false},{"id":269934,"name":"Zifei Pei","orcid":"0009-0004-6484-6547","position":5,"is_corresponding":false},{"id":269935,"name":"Mei Jiang","orcid":"0000-0002-9111-0410","position":6,"is_corresponding":false},{"id":269936,"name":"Yuting Bai","orcid":"0000-0001-6079-1340","position":7,"is_corresponding":false},{"id":272603,"name":"Cody Forsyth","orcid":null,"position":8,"is_corresponding":false},{"id":272604,"name":"Morgan Metzger","orcid":null,"position":9,"is_corresponding":false},{"id":272605,"name":"Tanvi Rana","orcid":null,"position":10,"is_corresponding":false},{"id":269937,"name":"Lei Zhang","orcid":"0000-0001-7439-9534","position":11,"is_corresponding":false},{"id":269938,"name":"Xiaoyun Ding","orcid":"0000-0002-9786-6630","position":12,"is_corresponding":false},{"id":269939,"name":"Matthew G. 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