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Conversion of Reactive Astrocytes to Induced Neurons Enhances Neuronal Repair and Functional Recovery After Ischemic Stroke

The master neuronal transcription factor NeuroD1 can directly reprogram astrocytes into induced neurons (iNeurons) after stroke. Using viral vectors to drive ectopic ND1 expression in gliotic astrocytes after brain injury presents an autologous form of cell therapy for neurodegenerative disease. Cul...

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Autores principales: Jiang, Michael Qize, Yu, Shan Ping, Wei, Zheng Zachory, Zhong, Weiwei, Cao, Wenyuan, Gu, Xiaohuan, Wu, Anika, McCrary, Myles Randolph, Berglund, Ken, Wei, Ling
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032905/
https://www.ncbi.nlm.nih.gov/pubmed/33841125
http://dx.doi.org/10.3389/fnagi.2021.612856
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author Jiang, Michael Qize
Yu, Shan Ping
Wei, Zheng Zachory
Zhong, Weiwei
Cao, Wenyuan
Gu, Xiaohuan
Wu, Anika
McCrary, Myles Randolph
Berglund, Ken
Wei, Ling
author_facet Jiang, Michael Qize
Yu, Shan Ping
Wei, Zheng Zachory
Zhong, Weiwei
Cao, Wenyuan
Gu, Xiaohuan
Wu, Anika
McCrary, Myles Randolph
Berglund, Ken
Wei, Ling
author_sort Jiang, Michael Qize
collection PubMed
description The master neuronal transcription factor NeuroD1 can directly reprogram astrocytes into induced neurons (iNeurons) after stroke. Using viral vectors to drive ectopic ND1 expression in gliotic astrocytes after brain injury presents an autologous form of cell therapy for neurodegenerative disease. Cultured astrocytes transfected with ND1 exhibited reduced proliferation and adopted neuronal morphology within 2–3 weeks later, expressed neuronal/synaptic markers, and extended processes. Whole-cell recordings detected the firing of evoked action potentials in converted iNeurons. Focal ischemic stroke was induced in adult GFAP-Cre-Rosa-YFP mice that then received ND1 lentivirus injections into the peri-infarct region 7 days after stroke. Reprogrammed cells did not express stemness genes, while 2–6 weeks later converted cells were co-labeled with YFP (constitutively activated in astrocytes), mCherry (ND1 infection marker), and NeuN (mature neuronal marker). Approximately 66% of infected cells became NeuN-positive neurons. The majority (~80%) of converted cells expressed the vascular glutamate transporter (vGLUT) of glutamatergic neurons. ND1 treatment reduced astrogliosis, and some iNeurons located/survived inside of the savaged ischemic core. Western blotting detected higher levels of BDNF, FGF, and PSD-95 in ND1-treated mice. MultiElectrode Array (MEA) recordings in brain slices revealed that the ND1-induced reprogramming restored interrupted cortical circuits and synaptic plasticity. Furthermore, ND1 treatment significantly improved locomotor, sensorimotor, and psychological functions. Thus, conversion of endogenous astrocytes to neurons represents a plausible, on-site regenerative therapy for stroke.
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spelling pubmed-80329052021-04-10 Conversion of Reactive Astrocytes to Induced Neurons Enhances Neuronal Repair and Functional Recovery After Ischemic Stroke Jiang, Michael Qize Yu, Shan Ping Wei, Zheng Zachory Zhong, Weiwei Cao, Wenyuan Gu, Xiaohuan Wu, Anika McCrary, Myles Randolph Berglund, Ken Wei, Ling Front Aging Neurosci Neuroscience The master neuronal transcription factor NeuroD1 can directly reprogram astrocytes into induced neurons (iNeurons) after stroke. Using viral vectors to drive ectopic ND1 expression in gliotic astrocytes after brain injury presents an autologous form of cell therapy for neurodegenerative disease. Cultured astrocytes transfected with ND1 exhibited reduced proliferation and adopted neuronal morphology within 2–3 weeks later, expressed neuronal/synaptic markers, and extended processes. Whole-cell recordings detected the firing of evoked action potentials in converted iNeurons. Focal ischemic stroke was induced in adult GFAP-Cre-Rosa-YFP mice that then received ND1 lentivirus injections into the peri-infarct region 7 days after stroke. Reprogrammed cells did not express stemness genes, while 2–6 weeks later converted cells were co-labeled with YFP (constitutively activated in astrocytes), mCherry (ND1 infection marker), and NeuN (mature neuronal marker). Approximately 66% of infected cells became NeuN-positive neurons. The majority (~80%) of converted cells expressed the vascular glutamate transporter (vGLUT) of glutamatergic neurons. ND1 treatment reduced astrogliosis, and some iNeurons located/survived inside of the savaged ischemic core. Western blotting detected higher levels of BDNF, FGF, and PSD-95 in ND1-treated mice. MultiElectrode Array (MEA) recordings in brain slices revealed that the ND1-induced reprogramming restored interrupted cortical circuits and synaptic plasticity. Furthermore, ND1 treatment significantly improved locomotor, sensorimotor, and psychological functions. Thus, conversion of endogenous astrocytes to neurons represents a plausible, on-site regenerative therapy for stroke. Frontiers Media S.A. 2021-03-26 /pmc/articles/PMC8032905/ /pubmed/33841125 http://dx.doi.org/10.3389/fnagi.2021.612856 Text en Copyright © 2021 Jiang, Yu, Wei, Zhong, Cao, Gu, Wu, McCrary, Berglund and Wei. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Jiang, Michael Qize
Yu, Shan Ping
Wei, Zheng Zachory
Zhong, Weiwei
Cao, Wenyuan
Gu, Xiaohuan
Wu, Anika
McCrary, Myles Randolph
Berglund, Ken
Wei, Ling
Conversion of Reactive Astrocytes to Induced Neurons Enhances Neuronal Repair and Functional Recovery After Ischemic Stroke
title Conversion of Reactive Astrocytes to Induced Neurons Enhances Neuronal Repair and Functional Recovery After Ischemic Stroke
title_full Conversion of Reactive Astrocytes to Induced Neurons Enhances Neuronal Repair and Functional Recovery After Ischemic Stroke
title_fullStr Conversion of Reactive Astrocytes to Induced Neurons Enhances Neuronal Repair and Functional Recovery After Ischemic Stroke
title_full_unstemmed Conversion of Reactive Astrocytes to Induced Neurons Enhances Neuronal Repair and Functional Recovery After Ischemic Stroke
title_short Conversion of Reactive Astrocytes to Induced Neurons Enhances Neuronal Repair and Functional Recovery After Ischemic Stroke
title_sort conversion of reactive astrocytes to induced neurons enhances neuronal repair and functional recovery after ischemic stroke
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032905/
https://www.ncbi.nlm.nih.gov/pubmed/33841125
http://dx.doi.org/10.3389/fnagi.2021.612856
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