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Conversion of human glial cells into neurons in ex vivo culture of human brain tissue:Essential roles of the transcription factors NeuroD1 and Ascl1 认领 引用
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作者 Liang Xu Qingsong Wang +8 位作者 Jiancheng Liao Jiajun Zheng Bing Qin Wen Li Jiaxuan Zhang Wei Li Xiangyu Wang Maoying Zhang Gong Chen 《Neural Regeneration Research》 SCIE CAS CSCD 2026年第8期3650-3658,共9页
Transcription factor-mediated cell conversion has been reported in the central nervous system of both rodents and nonhuman primates.In particular,glia-to-neuron conversion has been achieved in the brain and spinal cor... Transcription factor-mediated cell conversion has been reported in the central nervous system of both rodents and nonhuman primates.In particular,glia-to-neuron conversion has been achieved in the brain and spinal cord of animal models for neural regeneration and repair.However,whether glia-to-neuron conversion can be used for brain repair in humans needs to be explored.To investigate the use of glia-to-neuron conversion technology in the human brain,we established a long-term ex vivo culture system using human brain tissue that was surgically removed from epileptic patients to test glia-to-neuron conversion directly.We found that neural transcription factors NeuroD1 and Ascl1 both converted human glial cells into neurons.Immunostaining and electrophysiological recordings showed that the glia-converted neurons demonstrated immature properties during the initial 7-14 days of conversion,and then acquired more mature neuronal properties after 21-27 days of conversion.These ex vivo conversion studies in human brain tissue pave the way toward future clinical trials using a transcription factor-based glia-to-neuron conversion approach to treat neurological disorders. 展开更多
关键词 Ascl1 brain slice cell conversion ex vivo culture glial cell glia-to-neuron conversion human brain in vivo reprogramming neural regeneration NeuroD1
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Characteristic changes in astrocyte properties during astrocyte-to-neuron conversion induced by NeuroD1/Ascl1/Dlx2 认领 引用 被引量：4
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作者 Qing He Zhen Wang +5 位作者 Yuchen Wang Mengjie Zhu Zhile Liang Kanghong Zhang Yuge Xu Gong Chen 《Neural Regeneration Research》 SCIE CAS CSCD 2025年第6期1801-1815,共15页
Direct in vivo conversion of astrocytes into functional new neurons induced by neural transcription factors has been recognized as a potential new therapeutic intervention for neural injury and degenerative disorders.... Direct in vivo conversion of astrocytes into functional new neurons induced by neural transcription factors has been recognized as a potential new therapeutic intervention for neural injury and degenerative disorders. However, a few recent studies have claimed that neural transcription factors cannot convert astrocytes into neurons, attributing the converted neurons to pre-existing neurons mis-expressing transgenes. In this study, we overexpressed three distinct neural transcription factors––NeuroD1, Ascl1, and Dlx2––in reactive astrocytes in mouse cortices subjected to stab injury, resulting in a series of significant changes in astrocyte properties. Initially, the three neural transcription factors were exclusively expressed in the nuclei of astrocytes. Over time, however, these astrocytes gradually adopted neuronal morphology, and the neural transcription factors was gradually observed in the nuclei of neuron-like cells instead of astrocytes. Furthermore,we noted that transcription factor-infected astrocytes showed a progressive decrease in the expression of astrocytic markers AQP4(astrocyte endfeet signal), CX43(gap junction signal), and S100β. Importantly, none of these changes could be attributed to transgene leakage into preexisting neurons. Therefore, our findings suggest that neural transcription factors such as NeuroD1, Ascl1, and Dlx2 can effectively convert reactive astrocytes into neurons in the adult mammalian brain. 展开更多
关键词 aquaporin-4 Ascl1 astrocyte cortex Dlx2 gap junction glia-to-neuron conversion neural regeneration NeuroD1 reprogramming
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Lineage tracing of direct astrocyte-to-neuron conversion in the mouse cortex 认领 引用 被引量：20
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作者 Zongqin Xiang Liang Xu +4 位作者 Minhui Liu Qingsong Wang Wen Li Wenliang Lei Gong Chen 《Neural Regeneration Research》 SCIE CAS CSCD 2021年第4期750-756,共7页
Regenerating functional new neurons in the adult mammalian central nervous system has been proven to be very challenging due to the inability of neurons to divide and repopulate themselves after neuronal loss.Glial ce... Regenerating functional new neurons in the adult mammalian central nervous system has been proven to be very challenging due to the inability of neurons to divide and repopulate themselves after neuronal loss.Glial cells,on the other hand,can divide and repopulate themselves under injury or diseased conditions.We have previously reported that ectopic expression of NeuroD1 in dividing glial cells can directly convert them into neurons.Here,using astrocytic lineage-tracing reporter mice(Aldh1l1-CreERT2 mice crossing with Ai14 mice),we demonstrate that lineage-traced astrocytes can be successfully converted into NeuNpositive neurons after expressing NeuroD1 through adeno-associated viruses.Retroviral expression of NeuroD1 further confirms that dividing glial cells can be converted into neurons.Importantly,we demonstrate that for in vivo cell conversion study,using a safe level of adeno-associated virus dosage(10^10–10^12 gc/mL,1μL)in the rodent brain is critical to avoid artifacts caused by toxic dosage,such as that used in a recent bioRxiv study(2×10^13 gc/mL,1μL,mouse cortex).For therapeutic purpose under injury or diseased conditions,or for non-human primate studies,adeno-associated virus dosage needs to be optimized through a series of dose-finding experiments.Moreover,for future in vivo gliato-neuron conversion studies,we recommend that the adeno-associated virus results are further verified with retroviruses that mainly express transgenes in dividing glial cells in order to draw solid conclusions.The study was approved by the Laboratory Animal Ethics Committee of Jinan University,China(approval No.IACUC-20180330-06)on March 30,2018. 展开更多
关键词 adeno-associated viruses astrocyte dosage glia-to-neuron conversion in vivo reprogramming lineage tracing neuron retrovirus
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Versatile strategies for adult neurogenesis:avenues to repair the injured brain 认领 引用 被引量：3
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作者 Junyi Zhao Siyu Liu +1 位作者 Xianyuan Xiang Xinzhou Zhu 《Neural Regeneration Research》 SCIE CAS CSCD 2024年第4期774-780,共7页
Brain injuries due to trauma or stroke are major causes of adult death and disability.Unfortunately,few interventions are effective for post-injury repair of brain tissue.After a long debate on whether endogenous neur... Brain injuries due to trauma or stroke are major causes of adult death and disability.Unfortunately,few interventions are effective for post-injury repair of brain tissue.After a long debate on whether endogenous neurogenesis actually happens in the adult human brain,there is now substantial evidence to support its occurrence.Although neurogenesis is usually significantly stimulated by injury,the reparative potential of endogenous differentiation from neural stem/progenitor cells is usually insufficient.Alternatively,exogenous stem cell transplantation has shown promising results in animal models,but limitations such as poor long-term survival and inefficient neuronal differentiation make it still challenging for clinical use.Recently,a high focus was placed on glia-to-neuron conversion under single-factor regulation.Despite some inspiring results,the validity of this strategy is still controversial.In this review,we summarize historical findings and recent advances on neurogenesis strategies for neurorepair after brain injury.We also discuss their advantages and drawbacks,as to provide a comprehensive account of their potentials for further studies. 展开更多
关键词 adult neurogenesis glia-to-neuron conversion ischemic stroke neurogenic niche neuroinflammation stem cell transplantation traumatic brain injury
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Post-transcriptional mechanisms controlling neurogenesis and direct neuronal reprogramming 认领 引用 被引量：2
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作者 Elsa Papadimitriou Dimitra Thomaidou 《Neural Regeneration Research》 SCIE CAS CSCD 2024年第9期1929-1939,共11页
Neurogenesis is a tightly regulated process in time and space both in the developing embryo and in adult neurogenic niches.A drastic change in the transcriptome and proteome of radial glial cells or neural stem cells ... Neurogenesis is a tightly regulated process in time and space both in the developing embryo and in adult neurogenic niches.A drastic change in the transcriptome and proteome of radial glial cells or neural stem cells towards the neuronal state is achieved due to sophisticated mechanisms of epigenetic,transcriptional,and post-transcriptional regulation.Understanding these neurogenic mechanisms is of major importance,not only for shedding light on very complex and crucial developmental processes,but also for the identification of putative reprogramming factors,that harbor hierarchically central regulatory roles in the course of neurogenesis and bare thus the capacity to drive direct reprogramming towards the neuronal fate.The major transcriptional programs that orchestrate the neurogenic process have been the focus of research for many years and key neurogenic transcription factors,as well as repressor complexes,have been identified and employed in direct reprogramming protocols to convert non-neuronal cells,into functional neurons.The post-transcriptional regulation of gene expression during nervous system development has emerged as another important and intricate regulatory layer,strongly contributing to the complexity of the mechanisms controlling neurogenesis and neuronal function.In particular,recent advances are highlighting the importance of specific RNA binding proteins that control major steps of mRNA life cycle during neurogenesis,such as alternative splicing,polyadenylation,stability,and translation.Apart from the RNA binding proteins,microRNAs,a class of small non-coding RNAs that block the translation of their target mRNAs,have also been shown to play crucial roles in all the stages of the neurogenic process,from neural stem/progenitor cell proliferation,neuronal differentiation and migration,to functional maturation.Here,we provide an overview of the most prominent post-transcriptional mechanisms mediated by RNA binding proteins and microRNAs during the neurogenic process,giving particular emphasis on the interplay of specific RNA binding proteins with neurogenic microRNAs.Taking under consideration that the molecular mechanisms of neurogenesis exert high similarity to the ones driving direct neuronal reprogramming,we also discuss the current advances in in vitro and in vivo direct neuronal reprogramming approaches that have employed microRNAs or RNA binding proteins as reprogramming factors,highlighting the so far known mechanisms of their reprogramming action. 展开更多
关键词 direct neuronal reprogramming in vivo glia-to-neuron conversion microRNAs neurogenesis post-transcriptional regulation RNA binding proteins
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