Background Parkinson’s disease(PD)is one of the neurodegeneration diseases characterized by the gradual loss of dopaminergic(DA)neurons in the substantia nigra region of the brain.Substantial evidence indicates that ...Background Parkinson’s disease(PD)is one of the neurodegeneration diseases characterized by the gradual loss of dopaminergic(DA)neurons in the substantia nigra region of the brain.Substantial evidence indicates that at the cellular level mitochondrial dysfunction is a key factor leading to pathological features such as neuronal death and accumulation of misfoldedα-synuclein aggregations.Autologous transplantation of healthy purified mitochondria has shown to attenuate phenotypes in vitro and in vivo models of PD.However,there are significant technical difficulties in obtaining large amounts of purified mitochondria with normal function.In addition,the half-life of mitochondria varies between days to a few weeks.Thus,identifying a continuous source of healthy mitochondria via intercellular mitochondrial transfer is an attractive option for therapeutic purposes.In this study,we asked whether iPSCs derived astrocytes can serve as a donor to provide functional mitochondria and rescue injured DA neurons after rotenone exposure in an in vitro model of PD.Methods We generated DA neurons and astrocytes from human iPSCs and hESCs.We established an astroglial-neuronal co-culture system to investigate the intercellular mitochondrial transfer,as well as the neuroprotective effect of mitochondrial transfer.We employed immunocytochemistry and FACS analysis to track mitochondria.Results We showed evidence that iPSCs-derived astrocytes or astrocytic conditioned media(ACM)can rescue DA neurons degeneration via intercellular mitochondrial transfer in a rotenone induced in vitro PD model.Specifically,we showed that iPSCs-derived astrocytes from health spontaneously release functional mitochondria into the media.Mito-Tracker Green tagged astrocytic mitochondria were detected in the ACM and were shown to be internalized by the injured neurons via a phospho-p38 depended pathway.Transferred mitochondria were able to significantly reverse DA neurodegeneration and axonal pruning following exposure to rotenone.When rotenone injured neurons were cultured in presence of ACM depleted of mitochondria(by ultrafiltration),the neuroprotective effects were abolished.Conclusions Our studies provide the proof of principle that iPSCs-derived astrocytes can act as mitochondria donor to the injured DA neurons and attenuate pathology.Using iPSCs derived astrocytes as a donor can provide a novel strategy that can be further developed for cellular therapy for PD.展开更多
Alzheimer’s disease(AD)is a neurodegenerative disease that currently cannot be cured by any drug or intervention,due to its complicated pathogenesis.Current animal and cellular models of AD are unable to meet researc...Alzheimer’s disease(AD)is a neurodegenerative disease that currently cannot be cured by any drug or intervention,due to its complicated pathogenesis.Current animal and cellular models of AD are unable to meet research needs for AD.However,recent three-dimensional(3D)cerebral organoid models derived from human stem cells have provided a new tool to study molecular mechanisms and pharmaceutical developments of AD.In this review,we discuss the advantages and key limitations of the AD cerebral organoid system in comparison to the commonly used AD models,and propose possible solutions,in order to improve their application in AD research.Ethical concerns associated with human cerebral organoids are also discussed.We also summarize future directions of studies that will improve the cerebral organoid system to better model the pathological events observed in AD brains.展开更多
基金This work was in part supported by grants from RO1HD087566,RO1HD091325National Natural Science Foundation of China(81801258)+1 种基金Youth fund of Jiangsu Province’s natural science foundation(BK20170355)Gusu Health Talents Training Project(GSWS2019041).
文摘Background Parkinson’s disease(PD)is one of the neurodegeneration diseases characterized by the gradual loss of dopaminergic(DA)neurons in the substantia nigra region of the brain.Substantial evidence indicates that at the cellular level mitochondrial dysfunction is a key factor leading to pathological features such as neuronal death and accumulation of misfoldedα-synuclein aggregations.Autologous transplantation of healthy purified mitochondria has shown to attenuate phenotypes in vitro and in vivo models of PD.However,there are significant technical difficulties in obtaining large amounts of purified mitochondria with normal function.In addition,the half-life of mitochondria varies between days to a few weeks.Thus,identifying a continuous source of healthy mitochondria via intercellular mitochondrial transfer is an attractive option for therapeutic purposes.In this study,we asked whether iPSCs derived astrocytes can serve as a donor to provide functional mitochondria and rescue injured DA neurons after rotenone exposure in an in vitro model of PD.Methods We generated DA neurons and astrocytes from human iPSCs and hESCs.We established an astroglial-neuronal co-culture system to investigate the intercellular mitochondrial transfer,as well as the neuroprotective effect of mitochondrial transfer.We employed immunocytochemistry and FACS analysis to track mitochondria.Results We showed evidence that iPSCs-derived astrocytes or astrocytic conditioned media(ACM)can rescue DA neurons degeneration via intercellular mitochondrial transfer in a rotenone induced in vitro PD model.Specifically,we showed that iPSCs-derived astrocytes from health spontaneously release functional mitochondria into the media.Mito-Tracker Green tagged astrocytic mitochondria were detected in the ACM and were shown to be internalized by the injured neurons via a phospho-p38 depended pathway.Transferred mitochondria were able to significantly reverse DA neurodegeneration and axonal pruning following exposure to rotenone.When rotenone injured neurons were cultured in presence of ACM depleted of mitochondria(by ultrafiltration),the neuroprotective effects were abolished.Conclusions Our studies provide the proof of principle that iPSCs-derived astrocytes can act as mitochondria donor to the injured DA neurons and attenuate pathology.Using iPSCs derived astrocytes as a donor can provide a novel strategy that can be further developed for cellular therapy for PD.
基金This review was supported in part by grants from the Key R&D Program of Ningxia(2018BFG02005 to J.L.,2021BEG03100 to Y.Y.)the National Natural Science Foundation of China(82060792 and 81660645 to Y.Y.,81660673 to J.L.)+2 种基金the Natural Science Foundation of Ningxia(2020AAC03133 to Y.Y.,2021AAC03143 to J.L.)the Fourth Batch of Ningxia Youth Talents Supporting Program(TJGC2019091 to J.L.,TJGC2019100 to Y.Y.)the National College Students Innovation and Entrepreneurship Training Program(S202010752039 to F-C.B.).
文摘Alzheimer’s disease(AD)is a neurodegenerative disease that currently cannot be cured by any drug or intervention,due to its complicated pathogenesis.Current animal and cellular models of AD are unable to meet research needs for AD.However,recent three-dimensional(3D)cerebral organoid models derived from human stem cells have provided a new tool to study molecular mechanisms and pharmaceutical developments of AD.In this review,we discuss the advantages and key limitations of the AD cerebral organoid system in comparison to the commonly used AD models,and propose possible solutions,in order to improve their application in AD research.Ethical concerns associated with human cerebral organoids are also discussed.We also summarize future directions of studies that will improve the cerebral organoid system to better model the pathological events observed in AD brains.