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Neuronal conversion from glia to replenish the lost neurons

neural regeneration Research 2024年第7期19卷 1446-1453页

作者： Shiyu Liang Jing Zhou Xiaolin Yu Shuai Lu Ruitian Liu National key laboratory of Biochemical Engineering Institute of Process EngineeringChinese Academy of SciencesBeijingChina School of Chemical Engineering University of Chinese Academy of SciencesBeijingChina Department of Geriatric Rehabilitation Beijing Rehabilitation HospitalCapital Medical UniversityBeijingChina

Neuronal injury,aging,and cerebrovascular and neurodegenerative diseases such as cerebral infarction,Alzheimer’s disease,Parkinson’s disease,frontotemporal dementia,amyotrophic lateral sclerosis,and Huntington’s disease are characte rized by significant neuronal *** rtunately,the neurons of most mammals including humans do not possess the ability to *** of lost neurons becomes an appealing therapeutic strategy to reve rse the disease *** of pluripotent neural stem cells can supplement the missing neurons in the brain,but it carries the risk of causing gene mutation,tumorigenesis,severe inflammation,and obstructive hydrocephalus induced by brain *** of neural or non-neural lineage cells into functional neurons is a promising strategy for the diseases involving neuron loss,which may overcome the above-mentioned disadvantages of neural stem cell *** far,many strategies to transfo rm astrocytes,fibroblasts,microglia,Muller glia,NG2 cells,and other glial cells to mature and functional neurons,or for the conversion between neuronal subtypes have been developed thro ugh the regulation of transcription factors,polypyrimidine tra ct binding protein 1(PTBP1),and small chemical molecules or are based on a combination of several factors and the location in the central nervous ***,some recent papers did not obtain expected results,and discrepancies ***,in this review,we discuss the history of neuronal transdifferentiation,summarize the strategies for neuronal replenishment and conversion from glia,especially astrocytes,and point out that biosafety,new strategies,and the accurate origin of the truly co nverted neurons in vivo should be focused upon in future *** also arises the attention of replenishing the lost neurons from glia by gene therapies such as up-regulation of some transc ription factors or downregulation of PTBP1 or drug interfe rence therapies.

关键词： astrocytes neural stem cells neurodegenerative diseases neuron polypyrimidine tract binding protein 1 repair reprogramming small molecule transcription factor transdifferentiation

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Loss of Tet hydroxymethylase activity causes mouse embryonic stem cell differentiation bias and developmental defects

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Science China(Life Sciences) 2024年第10期67卷 2132-2148页

作者： Mengting Wang Liping Wang Yanxin Huang Zhibin Qiao Shanru Yi Weina Zhang Jing Wang Guang Yang Xinyu Cui Xiaochen Kou Yanhong Zhao Hong Wang Cizhong Jiang Shaorong Gao Jiayu Chen Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital Shanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China Shanghai Tenth People’s Hospital School of MedicineTongji UniversityShanghai 200072China Frontier Science Center for Stem Cell Research Tongji UniversityShanghai 200092China key laboratory of Spine and Spinal Cord Injury repair and regeneration of the Ministry of Education Orthopaedic Department of Tongji HospitalTongji UniversityShanghai 200065China Shanghai Institute of Stem Cell Research and Clinical Translation Shanghai 200120China

The TET family is well known for active DNA demethylation and plays important roles in regulating transcription,the epigenome and ***,previous studies using knockdown(KD)or knockout(KO)models to investigate the function of TET have faced challenges in distinguishing its enzymatic and nonenzymatic roles,as well as compensatory effects among TET family members,which has made the understanding of the enzymatic role of TET not accurate *** solve this problem,we successfully generated mice catalytically inactive for specific Tet members(Tetm/m).We observed that,compared with the reported KO mice,mutant mice exhibited distinct developmental defects,including growth retardation,sex imbalance,infertility,and perinatal ***,Tetm/mmouse embryonic stem cells(mESCs)were successfully established but entered an impaired developmental program,demonstrating extended pluripotency and defects in ectodermal differentiation caused by abnormal DNA ***,Tet3,traditionally considered less critical for m ESCs due to its lower expression level,had a significant impact on the global hydroxymethylation,gene expression,and differentiation potential of ***,there were common regulatory regions between Tet1 and Tet3 in pluripotency *** summary,our study provides a more accurate reference for the functional mechanism of Tet hydroxymethylase activity in mouse development and ESC pluripotency regulation.

关键词： Tet hydroxymethylase activity mESCs DNA demethylation 5hmC

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The burden of upper motor neuron involvement is correlated with the bilateral limb involvement interval in patients with amyotrophic lateral sclerosis:a retrospective observational study

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neural regeneration Research 2025年第5期20卷 1505-1512页

作者： Jieying Wu Shan Ye Xiangyi Liu Yingsheng Xu Dongsheng Fan Department of Neurology Peking University Third HospitalBeijingChina beijing Municipal key laboratory of Biomarker and Translational Research in Neurodegenerative Diseases BeijingChina key laboratory for Neuroscience National Health Commission/Ministry of EducationPeking UniversityBeijingChina

Amyotrophic lateral sclerosis is a rare neurodegenerative disease characterized by the involvement of both upper and lower motor *** bilateral limb involvement significantly affects patients'daily lives and may lead them to be confined to ***,the effect of upper and lower motor neuron impairment and other risk factors on bilateral limb involvement is *** address this issue,we retrospectively collected data from 586 amyotrophic lateral sclerosis patients with limb onset diagnosed at Peking University Third Hospital between January 2020 and May 2022.A univariate analysis revealed no significant differences in the time intervals of spread in different directions between individuals with upper motor neuron-dominant amyotrophic lateral sclerosis and those with classic amyotrophic lateral *** used causal directed acyclic graphs for risk factor determination and Cox proportional hazards models to investigate the association between the duration of bilateral limb involvement and clinical baseline characteristics in amyotrophic lateral sclerosis *** factor analyses revealed that higher upper motor neuron scores(hazard ratio[HR]=1.05,95%confidence interval[CI]=1.01–1.09,P=0.018),onset in the left limb(HR=0.72,95%CI=0.58–0.89,P=0.002),and a horizontal pattern of progression(HR=0.46,95%CI=0.37–0.58,P<0.001)were risk factors for a shorter interval until bilateral limb *** results demonstrated that a greater degree of upper motor neuron involvement might cause contralateral limb involvement to progress more quickly in limb-onset amyotrophic lateral sclerosis *** findings may improve the management of amyotrophic lateral sclerosis patients with limb onset and the prediction of patient prognosis.

关键词： amyotrophic lateral sclerosis bilateral limb involvement Cox proportional hazards regression model horizontal spread restricted cubic spline analysis time interval upper motor neuron vertical spread

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Multiple factors to assist human-derived induced pluripotent stem cells to efficiently differentiate into midbrain dopaminergic neurons

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neural regeneration Research 2024年第4期19卷 908-914页

作者： Yalan Chen Junxin Kuang Yimei Niu Hongyao Zhu Xiaoxia Chen Kwok-Fai So Anding Xu Lingling Shi Guangdong-Hong Kong-Macao Institute of CNS regeneration Ministry of Education CNS Regeneration Collaborative Joint LaboratoryJinan University Department of Neurology and Stroke Center The First Affiliated HospitalJinan University Department of Psychiatry The First Affiliated HospitalJinan University Co-innovation Center of Neuroregeneration Nantong University

Midbrain dopaminergic neurons play an important role in the etiology of neurodevelopmental and neurodegenerative *** also represent a potential source of transplanted cells for therapeutic *** vitro differentiation of functional midbrain dopaminergic neurons provides an accessible platform to study midbrain neuronal dysfunction and can be used to examine obstacles to dopaminergic neuronal *** evidence and impressive advances in human induced pluripotent stem cells,with tuned neural induction and differentiation protocols,makes the production of induced pluripotent stem cell-derived dopaminergic neurons *** SB431542 and dorsomorphin dual inhibitor in an induced pluripotent stem cell-derived neural induction protocol,we obtained multiple subtypes of neurons,including 20%tyrosine hydroxylase-positive dopaminergic *** obtain more dopaminergic neurons,we next added sonic hedgehog(SHH)and fibroblast growth factor 8(FGF8)on day 8 of *** increased the proportion of dopaminergic neurons,up to 75%tyrosine hydroxylase-positive neurons,with 15%tyrosine hydroxylase and forkhead box protein A2(FOXA2)co-expressing *** further optimized the induction protocol by applying the small molecule inhibitor,CHIR99021(CHIR).This helped facilitate the generation of midbrain dopaminergic neurons,and we obtained 31-74%midbrain dopaminergic neurons based on tyrosine hydroxylase and FOXA2 ***,we have established three induction protocols for dopaminergic *** on tyrosine hydroxylase and FOXA2 immunostaining analysis,the CHIR,SHH,and FGF8 combined protocol produces a much higher proportion of midbrain dopaminergic neurons,which could be an ideal resource for tackling midbrain-related diseases.

关键词： dopaminergic neurons FGF signal induced pluripotent stem cells midbrain neural differentiation SHH signal SMAD signal WNT signal

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Genetic pathways in cerebral palsy:a review of the implications for precision diagnosis and understanding disease mechanisms

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neural regeneration Research 2024年第7期19卷 1499-1508页

作者： Yiran Xu Yifei Li Seidu A.Richard Yanyan Sun Changlian Zhu Henan key laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center Institute of Neuroscience and The Third Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina National Health Council(NHC)key laboratory of Birth Defects Prevention Henan Key Laboratory of Population Defects PreventionZhengzhouHenan ProvinceChina Department of Human Anatomy School of Basic Medicine and Institute of NeuroscienceZhengzhou UniversityZhengzhouHenan ProvinceChina Center for Brain repair and Rehabilitation Institute of Neuroscience and PhysiologyUniversity of GothenburgGothenburgSweden

Ce rebral palsy is a diagnostic term utilized to describe a group of permanent disorders affecting movement and *** with cerebral palsy are often only capable of limited activity,resulting from non-progressive disturbances in the fetal or neonatal *** disturbances severely impact the child’s daily life and impose a substantial economic burden on the *** cerebral palsy encompasses various brain injuries leading to similar clinical outcomes,the unde rstanding of its etiological pathways remains incomplete owing to its complexity and *** review aims to summarize the current knowledge on the genetic factors influencing cerebral palsy *** is now widely acknowledged that genetic mutations and alterations play a pivotal role in cerebral palsy development,which can be further influenced by environmental fa *** pite continuous research endeavors,the underlying fa ctors contributing to cerebral palsy remain are still ***,significant progress has been made in genetic research that has markedly enhanced our comprehension of the genetic factors underlying cerebral palsy *** r,these genetic factors have been categorized based on the identified gene mutations in patients through clinical genotyping,including thrombosis,angiogenesis,mitochondrial and oxidative phosphorylation function,neuronal migration,and cellular ***,exploring targeted genotypes holds potential for precision *** conclusion,advancements in genetic research have substantially improved our understanding of the genetic causes underlying cerebral *** breakthroughs have the potential to pave the way for new treatments and therapies,consequently shaping the future of cerebral palsy research and its clinical *** investigation of cerebral palsy genetics holds the potential to significantly advance treatments and management *** elucidating the underlying cellular mechanisms,w

关键词： cerebral palsy environmental factors etiology genetic factors genetic mutation movement disorder spastic diplegia

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Hypidone hydrochloride(YL-0919)ameliorates functional deficits after traumatic brain injury in mice by activating the sigma-1 receptor for antioxidation

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neural regeneration Research 2025年第8期20卷 2325-2336页

作者： Yafan Bai Hui Ma Yue Zhang Jinfeng Li Xiaojuan Hou Yixin Yang Guyan Wang Yunfeng Li Department of Anesthesiology Beijing Tongren HospitalCapital Medical UniversityBeijingChina beijing Institute of Basic Medical Sciences BeijingChina Hebei North University ZhangjiakouHebei ProvinceChina beijing Institute of Pharmacology and Toxicology State Key Laboratory of Toxicology and Medical CountermeasuresBeijing Key Laboratory of NeuropsychopharmacologyBeijingChina

Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary *** this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain *** experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain ***,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 ***,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain ***,YL-0919 effectively combated oxidative stress both in vivo and in *** protective effects of YL-0919 were partially inhibited by *** results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist ***-0919 may have potential as a new treatment for traumatic brain injury.

关键词： antidepressant drug blood-brain barrier cognitive function hypidone hydrochloride(YL-0919) neurological function nuclear factor-erythroid 2 related factor 2 oxidative stress sigma-1 receptor superoxide dismutase traumatic brain injury

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Role of the globus pallidus in motor and non-motor symptoms of Parkinson's disease

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neural regeneration Research 2025年第6期20卷 1628-1643页

作者： Yimiao Jiang Zengxin Qi Huixian Zhu Kangli Shen Ruiqi Liu Chenxin Fang Weiwei Lou Yifan Jiang Wangrui Yuan Xin Cao Liang Chen Qianxing Zhuang Department of Physiology School of MedicineNantong UniversityNantongJiangsu ProvinceChina Department of Neurosurgery Huashan HospitalShanghai Medical CollegeFudan UniversityShanghaiChina National Center for Neurological Disorders ShanghaiChina Shanghai key laboratory of Brain Function Restoration and neural regeneration ShanghaiChina State key laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science Institute of Brain ScienceFudan UniversityShanghaiChina

The globus pallidus plays a pivotal role in the basal ganglia circuit. Parkinson's disease is characterized by degeneration of dopamine-producing cells in the substantia nigra, which leads to dopamine deficiency in the brain that subsequently manifests as various motor and non-motor symptoms. This review aims to summarize the involvement of the globus pallidus in both motor and non-motor manifestations of Parkinson's disease. The firing activities of parvalbumin neurons in the medial globus pallidus, including both the firing rate and pattern, exhibit strong correlations with the bradykinesia and rigidity associated with Parkinson's disease. Increased beta oscillations, which are highly correlated with bradykinesia and rigidity, are regulated by the lateral globus pallidus. Furthermore,bradykinesia and rigidity are strongly linked to the loss of dopaminergic projections within the cortical-basal ganglia-thalamocortical loop. Resting tremors are attributed to the transmission of pathological signals from the basal ganglia through the motor cortex to the cerebellum-ventral intermediate nucleus circuit. The cortico–striato–pallidal loop is responsible for mediating pallidi-associated sleep disorders. Medication and deep brain stimulation are the primary therapeutic strategies addressing the globus pallidus in Parkinson's disease. Medication is the primary treatment for motor symptoms in the early stages of Parkinson's disease, while deep brain stimulation has been clinically proven to be effective in alleviating symptoms in patients with advanced Parkinson's disease,particularly for the movement disorders caused by levodopa. Deep brain stimulation targeting the globus pallidus internus can improve motor function in patients with tremordominant and non-tremor-dominant Parkinson's disease, while deep brain stimulation targeting the globus pallidus externus can alter the temporal pattern of neural activity throughout the basal ganglia–thalamus network. Therefore, the comp

关键词： anxiety basal ganglia bradykinesia deep brain stimulation depression globus pallidus externus globus pallidus internus lateral globus pallidus medial globus pallidus neural circuit Parkinson's disease

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MDGA2 Constrains Glutamatergic Inputs Selectively onto CA1 Pyramidal Neurons to Optimize neural Circuits for Plasticity,Memory,and Social Behavior

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Neuroscience Bulletin 2024年第7期40卷 887-904页

作者： Xuehui Wang Donghui Lin Jie Jiang Yuhua Liu Xinyan Dong Jianchen Fan Lifen Gong Weida Shen Linghui Zeng Tonghui Xu Kewen Jiang Steven A.Connor Yicheng Xie School of Life Sciences Nanchang UniversityNanchang330031China Department of Neurology Children's HospitalZhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhou 310052China Department of Biology York University4700 Keele StreetTorontoON M3J 1P3Canada key laboratory of Novel Targets and Drug Study for neural repair of Zhejiang Province School of MedicineHangzhou City UniversityHangzhou 310015China

Synapse organizers are essential for the development,transmission,and plasticity of *** as rare synapse suppressors,the MAM domain containing glycosylphosphatidylinositol anchor(MDGA)proteins contributes to synapse organization by inhibiting the formation of the synaptogenic neuroligin-neurexin complex.A previous analysis of MDGA2 mice lacking a single copy of Mdga2 revealed upregulated glutamatergic synapses and behaviors consistent with ***,MDGA2 is expressed in diverse cell types and is localized to both excitatory and inhibitory *** the network versus cell-specific effects of MDGA2 loss-of-function requires a cell-type and brain region-selective *** address this,we generated mice harboring a conditional knockout of Mdga2 restricted to CA1 pyramidal *** we report that MDGA2 suppresses the density and function of excitatory synapses selectively on pyramidal neurons in the mature *** deletion of Mdga2 in CA1 pyramidal neurons of adult mice upregulated miniature and spontaneous excitatory postsynaptic potentials,vesicular glutamate transporter 1 intensity,and neuronal *** effects were limited to glutamatergic synapses as no changes were detected in miniature and spontaneous inhibitory postsynaptic potential properties or vesicular GABA transporter ***,evoked basal synaptic transmission and AMPAR receptor currents were enhanced at glutamatergic *** a behavioral level,memory appeared to be compromised in Mdga2 cKO mice as both novel object recognition and contextual fear conditioning performance were impaired,consistent with deficits in long-term potentiation in the CA3-CA1 *** affiliation,a behavioral analog of social deficits in autism,was similarly *** results demonstrate that MDGA2 confines the properties of excitatory synapses to CA1 neurons in mature hippocampal circuits,thereby optimizing this network for plasticity,c

关键词： MDGA2 CA1 pyramidal neurons Glutamatergic inputs Synaptic plasticity Memory Social behaviors Autism Synapse organizers

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In situ forming injectable MSC-loaded GelMA hydrogels combined with PD for vascularized sweat gland regeneration

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Military Medical Research 2024年第1期11卷 152-155页

作者： Enhe Jirigala Bin Yao Zhao Li Yi-Jie Zhang Chao Zhang Li-Ting Liang Fan-Liang Zhang Xing-Yu Yuan Xian-Lan Duan Wei Song Meng-De Zhang Yi Kong Xiao-Bing Fu Sha Huang Research Center for Tissue repair and regeneration Medical Innovation Research DepartmentChinese PLA General Hospital and PLA Medical CollegeBeijing 100048China Institute of Basic Medical Research Inner Mongolia Medical UniversityHohhot 010110China Academy of Medical Engineering and Translational Medicine Tianjin UniversityTianjin 300072China School of Medicine Nankai UniversityTianjin 300071China

Dear Editor,Three dimensional(3D)bioprinted extracellular matrix(ECM)can be used to provide both biochemical and biophysical cues to direct mesenchymal stem cells(MSCs)differentiation,and then differentiated cells were isolated for implantation in vivo using surgical ***,the reduced cell activity after cell isolation from 3D constructs and low cell retention in injured sites limit its application[1].Methacrylated gelatin(GelMA)hydrogel has the advantage of fast crosslinking,which could resemble complex architectures of tissue construct in vivo[2].Here,we adopted a noninvasive bioprinting procedure to imitate the regenerative microenvironment that could simultaneously direct the sweat gland(SG)and vascular differentiation from MSCs and ultimately promote the replacement of glandular tissue in situ(Fig.1a).

关键词： Sweat gland GelMA In situ niche Cell differentiation Tissue incorporation Vascularization

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CD146,a therapeutic target involved in cell plasticity

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Science China(Life Sciences) 2024年第8期67卷 1563-1578页

作者： Zhenzhen Wu Yuzhe Zang Chuyi Li Zhiheng He Jingyu Liu Zhaoqi Du Xinran Ma Lin Jing Hongxia Duan Jing Feng Xiyun Yan CAS Engineering laboratory for Nanozyme Key Laboratory of BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China College of Life Sciences University of Chinese Academy of SciencesBeijing 100049China Nanozyme laboratory in Zhongyuan Henan Academy of Innovations in Medical ScienceZhengzhou 451163China Joint laboratory of Nanozymes in Zhengzhou University School of Basic Medical SciencesZhengzhou UniversityZhengzhou 450001China

Since its identification as a marker for advanced melanoma in the 1980s,CD146 has been found to have multiple functions in both physiological and pathological processes,including embryonic development,tissue repair and regeneration,tumor progression,fibrosis disease,and *** research has revealed that CD146 is involved in various signaling pathways as a receptor or coreceptor in these *** correlation between CD146 and multiple diseases has sparked interest in its potential applications in diagnosis,prognosis,and targeted *** better comprehend the versatile roles of CD146,we have summarized its research history and synthesized findings from numerous reports,proposing that cell plasticity serves as the underlying mechanism through which CD146 contributes to development,regeneration,and various *** CD146 would consequently halt cell state shifting during the onset and progression of these related ***,the development of therapy targeting CD146 holds significant practical value.

关键词： CD146 cell plasticity therapeutic target

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