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
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
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
基金supported by the SIAT Innovation Program for Excellent Young Researchers,No.E1G0241001(to XZ)。
文摘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.
基金supported by Stavros Niarhos FoundationGreek‘Flagship Action for the Study of Neurodegenerative Diseases on the Basis of Precision Medicine’(to DT).
文摘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.
基金This study was supported by the National Natural Science Foundation of China(No.U1801681,to GC and No.31970906,to WL)Guangdong Science and Technology Department(‘Key technologies for treatment of brain disorders’,No.2018B030332001,to GC)+2 种基金the Natural Science Foundation of Guangdong Province of China(No.2020A1515011079,to WL and No.2020A1515010854,to QW)the internal funding from Jinan University(No.21616110,to GC)the Young Scientists Fund of the National Natural Science Foundation of China(No.31701291,to WL).
文摘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.
