Advanced brain organoids provide promising platforms for deciphering the cellular and molecular processes of human neural development and diseases.Although various studies and reviews have described developments and a...Advanced brain organoids provide promising platforms for deciphering the cellular and molecular processes of human neural development and diseases.Although various studies and reviews have described developments and advancements in brain organoids,few studies have comprehensively summarized and analyzed the global trends in this area of neuroscience.To identify and further facilitate the development of cerebral organoids,we utilized bibliometrics and visualization methods to analyze the global trends and evolution of brain organoids in the last 10 years.First,annual publications,countries/regions,organizations,journals,authors,co-citations,and keywords relating to brain organoids were identified.The hotspots in this field were also systematically identified.Subsequently,current applications for brain organoids in neuroscience,including human neural development,neural disorders,infectious diseases,regenerative medicine,drug discovery,and toxicity assessment studies,are comprehensively discussed.Towards that end,several considerations regarding the current challenges in brain organoid research and future strategies to advance neuroscience will be presented to further promote their application in neurological research.展开更多
At the level of in vitro drug screening,the development of a phenotypic analysis system with highcontent screening at the core provides a strong platform to support high-throughput drug screening.There are few systema...At the level of in vitro drug screening,the development of a phenotypic analysis system with highcontent screening at the core provides a strong platform to support high-throughput drug screening.There are few systematic reports on brain organoids,as a new three-dimensional in vitro model,in terms of model stability,key phenotypic fingerprint,and drug screening schemes,and particula rly rega rding the development of screening strategies for massive numbers of traditional Chinese medicine monomers.This paper reviews the development of brain organoids and the advantages of brain organoids over induced neurons or cells in simulated diseases.The paper also highlights the prospects from model stability,induction criteria of brain organoids,and the screening schemes of brain organoids based on the characteristics of brain organoids and the application and development of a high-content screening system.展开更多
Understanding the fundamental processes of human brain development and diseases is of great importance for our health.However,existing research models such as non-human primate and mouse models remain limited due to t...Understanding the fundamental processes of human brain development and diseases is of great importance for our health.However,existing research models such as non-human primate and mouse models remain limited due to their developmental discrepancies compared with humans.Over the past years,an emerging model,the“brain organoid”integrated from human pluripotent stem cells,has been developed to mimic developmental processes of the human brain and disease-associated phenotypes to some extent,making it possible to better understand the complex structures and functions of the human brain.In this review,we summarize recent advances in brain organoid technologies and their applications in brain development and diseases,including neurodevelopmental,neurodegenerative,psychiatric diseases,and brain tumors.Finally,we also discuss current limitations and the potential of brain organoids.展开更多
Studying the etiology of human neurodevelopmental diseases has long been a challenging task due to the brain’s complexity and its limited accessibility.Human pluripotent stem cells(hPSCs)-derived brain organoids are ...Studying the etiology of human neurodevelopmental diseases has long been a challenging task due to the brain’s complexity and its limited accessibility.Human pluripotent stem cells(hPSCs)-derived brain organoids are capable of recapitulating various features and functionalities of the human brain,allowing the investigation of intricate patho-genesis of developmental abnormalities.Over the past years,brain organoids have facilitated identifying disease-associated phenotypes and underlying mechanisms for human neurodevelopmental diseases.Integrating with more cutting-edge technologies,particularly gene editing,brain organoids further empower human disease modeling.Here,we review the latest progress in modeling human neurodevelopmental disorders with brain organoids.展开更多
Early human brain development can be affected by multiple prenatal factors that involve chemical exposures in utero,maternal health characteristics such as psychiatric disorders,and cancer.Breast cancer is one of the ...Early human brain development can be affected by multiple prenatal factors that involve chemical exposures in utero,maternal health characteristics such as psychiatric disorders,and cancer.Breast cancer is one of the most common cancers worldwide arising pregnancy.However,it is not clear whether the breast cancer might influence the brain development of fetus.Exosomes secreted by breast cancer cells play a critical role in mediating intercellular communication and interplay between different organs.In this work,we engineered human induced pluripotent stem cells(hiPSCs)-derived brain organoids in an array of micropillar chip and probed the influences of breast cancer cell(MCF-7)derived-exosomes on the early neurodevelopment of brain.The formed brain organoids can recapitulate essential features of embryonic human brain at early stages,in terms of neurogenesis,forebrain regionalization,and cortical organization.Treatment with breast cancer cell derived-exosomes,brain organoids exhibited enhanced expression of stemness-related marker OCT4 and forebrain marker PAX6.RNA-seq analysis reflected several activated signaling pathways associated with breast cancer,medulloblastoma and neurogenesis in brain organoids induced by tumor-derived exosomes.These results suggested that breast cancer cell-derived exosomes might lead to the impaired neurodevelopment in the brain organoids and the carcinogenesis of brain organoids.It potentially implies the fetus of pregnant women with breast cancer has the risk of impaired neurodevelopmental disorder after birth.展开更多
As three-dimensional“organ-like”aggregates,human cortical organoids have emerged as powerful models for studying human brain evolution and brain disorders with unique advantages of humanspecificity,fidelity and mani...As three-dimensional“organ-like”aggregates,human cortical organoids have emerged as powerful models for studying human brain evolution and brain disorders with unique advantages of humanspecificity,fidelity and manipulation.Human cortical organoids derived from human pluripotent stem cells can elaborately replicate many of the key properties of human cortical development at the molecular,cellular,structural,and functional levels,including the anatomy,functional neural network,and interaction among different brain regions,thus facilitating the discovery of brain development and evolution.In addition to studying the neuro-electrophysiological features of brain cortex development,human cortical organoids have been widely used to mimic the pathophysiological features of cortical-related disease,especially in mimicking malformations of cortical development,thus revealing pathological mechanism and identifying effective drugs.In this review,we provide an overview of the generation of human cortical organoids and the properties of recapitulated cortical development and further outline their applications in modeling malformations of cortical development including pathological phenotype,underlying mechanisms and rescue strategies.展开更多
Multiple protocols have been devised to generate cerebral organoids that recapitulate features of the developing human brain, including the presence of a large, multi-layered, cortical-like neuronal zone. However, the...Multiple protocols have been devised to generate cerebral organoids that recapitulate features of the developing human brain, including the presence of a large, multi-layered, cortical-like neuronal zone. However, the central question is whether these organoids truly present mature, functional neurons and astrocytes, which may qualify the system for in-depth molecular neuroscience studies focused at neuronal and synaptic functions. Here, we demonstrate that cerebral organoids derived under optimal differentiation conditions exhibit mature, fully functional neurons and astrocytes, as validated by immunohistological, gene expression, and electrophysiological, analyses. Neurons in cerebral organoids showed gene expression profiles and electrophysiological properties similar to those reported for fetal human brain. These important findings indicate that cerebral organoids recapitulate the developing human brain and may enhance use of cerebral organoids in modeling human brain development or investigating neural deficits that underlie neurodevelopmental and neuropsychiatric conditions, such as autism or intellectual disorders.展开更多
The quest to find novel therapeutics for mental and neurological disorders has been hindered by the lack of access to l ive human brain samples and relevant experimental models. Conventional 2D human pluripotent st...The quest to find novel therapeutics for mental and neurological disorders has been hindered by the lack of access to l ive human brain samples and relevant experimental models. Conventional 2D human pluripotent stem cell-derived neuronal cultures and animal models do not ful ly recapitulate many endogenous human biochemical processes and disease phenotypes. Currently, the majority of candidate drugs obtained from preclinical testing in conventional systems does not usually translate into success and have a high failure rate in clinical trials. Recent advancements in bioengineering and stem cell technologies have resulted in three-dimensional brain-like tissues, such as oragnoids, which better resemble endogenous tissue and are more physiologically relevant than monolayer cultures. These brain-like tissues can bridge the gap between existing models and the patient, and may revolutionize the field of translational neuroscience. Here, we discuss utilities and challenges of using stem cell-derived human brain tissues in basic research and pharmacotherapy.展开更多
Brain diseases affect 1 in 6 people worldwide.These diseases range from acute neurological conditions such as stroke to chronic neurodegenerative disorders such as Alzheimer’s disease.Recent advancements in tissue-en...Brain diseases affect 1 in 6 people worldwide.These diseases range from acute neurological conditions such as stroke to chronic neurodegenerative disorders such as Alzheimer’s disease.Recent advancements in tissue-engineered brain disease models have overcome many of the different shortcomings associated with the various animal models,tissue culture models,and epidemiologic patient data that are commonly used to study brain disease.One innovative method by which to model human neurological disease is via the directed differentiation of human pluripotent stem cells(hPSCs)to neural lineages including neurons,astrocytes,and oligodendrocytes.Three-dimensional models such as brain organoids have also been derived from hPSCs,offering more physiological relevance due to their incorporation of various cell types.As such,brain organoids can better model the pathophysiology of neural diseases observed in patients.In this review,we will emphasize recent developments in hPSC-based tissue culture models of neurological disorders and how they are being used to create neural disease models.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82204083(to ML)and 12372303(to BW)the Natural Science Foundation of Chongqing,No.cstc2021jcy-jmsxmX0171(to ML).
文摘Advanced brain organoids provide promising platforms for deciphering the cellular and molecular processes of human neural development and diseases.Although various studies and reviews have described developments and advancements in brain organoids,few studies have comprehensively summarized and analyzed the global trends in this area of neuroscience.To identify and further facilitate the development of cerebral organoids,we utilized bibliometrics and visualization methods to analyze the global trends and evolution of brain organoids in the last 10 years.First,annual publications,countries/regions,organizations,journals,authors,co-citations,and keywords relating to brain organoids were identified.The hotspots in this field were also systematically identified.Subsequently,current applications for brain organoids in neuroscience,including human neural development,neural disorders,infectious diseases,regenerative medicine,drug discovery,and toxicity assessment studies,are comprehensively discussed.Towards that end,several considerations regarding the current challenges in brain organoid research and future strategies to advance neuroscience will be presented to further promote their application in neurological research.
基金supported by the National Natural Science Foundation of China,No.32000498the Startup Funding of Zhejiang University City College,No.210000-581849 (both to CG)National College Students’Innovative Entrepreneurial Training Plan Program,No.2021 13021024 (to JQZ)。
文摘At the level of in vitro drug screening,the development of a phenotypic analysis system with highcontent screening at the core provides a strong platform to support high-throughput drug screening.There are few systematic reports on brain organoids,as a new three-dimensional in vitro model,in terms of model stability,key phenotypic fingerprint,and drug screening schemes,and particula rly rega rding the development of screening strategies for massive numbers of traditional Chinese medicine monomers.This paper reviews the development of brain organoids and the advantages of brain organoids over induced neurons or cells in simulated diseases.The paper also highlights the prospects from model stability,induction criteria of brain organoids,and the screening schemes of brain organoids based on the characteristics of brain organoids and the application and development of a high-content screening system.
基金supported by the National Natural Science Foundation of China(32130035 and 92168107)STI2030-Major Projects(2021ZD0202500)+2 种基金the Frontier Key Project of the Chinese Academy of Sciences(QYZDJ-SSW-SMC025)Shanghai Municipal Science and Technology Projects(2018SHZDZX05)Shanghai Frontiers Science Center for Biomacromolecules and Precision Medicine at ShanghaiTech University.
文摘Understanding the fundamental processes of human brain development and diseases is of great importance for our health.However,existing research models such as non-human primate and mouse models remain limited due to their developmental discrepancies compared with humans.Over the past years,an emerging model,the“brain organoid”integrated from human pluripotent stem cells,has been developed to mimic developmental processes of the human brain and disease-associated phenotypes to some extent,making it possible to better understand the complex structures and functions of the human brain.In this review,we summarize recent advances in brain organoid technologies and their applications in brain development and diseases,including neurodevelopmental,neurodegenerative,psychiatric diseases,and brain tumors.Finally,we also discuss current limitations and the potential of brain organoids.
基金This work was supported by the Shanghai Pujiang Program(20PJ1410400)National Natural Science Foundation of China(32170836)the ShanghaiTech University start-up fund。
文摘Studying the etiology of human neurodevelopmental diseases has long been a challenging task due to the brain’s complexity and its limited accessibility.Human pluripotent stem cells(hPSCs)-derived brain organoids are capable of recapitulating various features and functionalities of the human brain,allowing the investigation of intricate patho-genesis of developmental abnormalities.Over the past years,brain organoids have facilitated identifying disease-associated phenotypes and underlying mechanisms for human neurodevelopmental diseases.Integrating with more cutting-edge technologies,particularly gene editing,brain organoids further empower human disease modeling.Here,we review the latest progress in modeling human neurodevelopmental disorders with brain organoids.
基金This study was supported by the National Key R&D Program of China(No.2017YFB0405404)the Strategic Priority Research Program of the Chinese Academy of Sciences(Nos.XDB32030200,XDB29050301,XDA16020900)+2 种基金National Nature Science Foundation of China(Nos.31971373,81803492)Innovation Program of Science and Research from the DICP,CAS(DICP I201934)Yunnan Key Research and Development Program(No.202003 AD150009).
文摘Early human brain development can be affected by multiple prenatal factors that involve chemical exposures in utero,maternal health characteristics such as psychiatric disorders,and cancer.Breast cancer is one of the most common cancers worldwide arising pregnancy.However,it is not clear whether the breast cancer might influence the brain development of fetus.Exosomes secreted by breast cancer cells play a critical role in mediating intercellular communication and interplay between different organs.In this work,we engineered human induced pluripotent stem cells(hiPSCs)-derived brain organoids in an array of micropillar chip and probed the influences of breast cancer cell(MCF-7)derived-exosomes on the early neurodevelopment of brain.The formed brain organoids can recapitulate essential features of embryonic human brain at early stages,in terms of neurogenesis,forebrain regionalization,and cortical organization.Treatment with breast cancer cell derived-exosomes,brain organoids exhibited enhanced expression of stemness-related marker OCT4 and forebrain marker PAX6.RNA-seq analysis reflected several activated signaling pathways associated with breast cancer,medulloblastoma and neurogenesis in brain organoids induced by tumor-derived exosomes.These results suggested that breast cancer cell-derived exosomes might lead to the impaired neurodevelopment in the brain organoids and the carcinogenesis of brain organoids.It potentially implies the fetus of pregnant women with breast cancer has the risk of impaired neurodevelopmental disorder after birth.
基金supported by the National Natural Science Foundation of China(Major Project),No.82030110(to CYM)the National Natural Science Foundation(Youth Program),No.82003754(to SNW)+1 种基金Medical Innovation Major Project,No.16CXZ009(to CYM)Shanghai Science and Technology Commission Projects,Nos.20YF1458400(to SNW)and 21140901000(to CYM)。
文摘As three-dimensional“organ-like”aggregates,human cortical organoids have emerged as powerful models for studying human brain evolution and brain disorders with unique advantages of humanspecificity,fidelity and manipulation.Human cortical organoids derived from human pluripotent stem cells can elaborately replicate many of the key properties of human cortical development at the molecular,cellular,structural,and functional levels,including the anatomy,functional neural network,and interaction among different brain regions,thus facilitating the discovery of brain development and evolution.In addition to studying the neuro-electrophysiological features of brain cortex development,human cortical organoids have been widely used to mimic the pathophysiological features of cortical-related disease,especially in mimicking malformations of cortical development,thus revealing pathological mechanism and identifying effective drugs.In this review,we provide an overview of the generation of human cortical organoids and the properties of recapitulated cortical development and further outline their applications in modeling malformations of cortical development including pathological phenotype,underlying mechanisms and rescue strategies.
文摘Multiple protocols have been devised to generate cerebral organoids that recapitulate features of the developing human brain, including the presence of a large, multi-layered, cortical-like neuronal zone. However, the central question is whether these organoids truly present mature, functional neurons and astrocytes, which may qualify the system for in-depth molecular neuroscience studies focused at neuronal and synaptic functions. Here, we demonstrate that cerebral organoids derived under optimal differentiation conditions exhibit mature, fully functional neurons and astrocytes, as validated by immunohistological, gene expression, and electrophysiological, analyses. Neurons in cerebral organoids showed gene expression profiles and electrophysiological properties similar to those reported for fetal human brain. These important findings indicate that cerebral organoids recapitulate the developing human brain and may enhance use of cerebral organoids in modeling human brain development or investigating neural deficits that underlie neurodevelopmental and neuropsychiatric conditions, such as autism or intellectual disorders.
文摘The quest to find novel therapeutics for mental and neurological disorders has been hindered by the lack of access to l ive human brain samples and relevant experimental models. Conventional 2D human pluripotent stem cell-derived neuronal cultures and animal models do not ful ly recapitulate many endogenous human biochemical processes and disease phenotypes. Currently, the majority of candidate drugs obtained from preclinical testing in conventional systems does not usually translate into success and have a high failure rate in clinical trials. Recent advancements in bioengineering and stem cell technologies have resulted in three-dimensional brain-like tissues, such as oragnoids, which better resemble endogenous tissue and are more physiologically relevant than monolayer cultures. These brain-like tissues can bridge the gap between existing models and the patient, and may revolutionize the field of translational neuroscience. Here, we discuss utilities and challenges of using stem cell-derived human brain tissues in basic research and pharmacotherapy.
基金CTSA Award from the National Center for Advancing Translational Sciences to the Vanderbilt Institute for Clinical and Translational Research,No.UL1 TR002243A Pilot and Feasibility Award from the NIDDK to the Vanderbilt Diabetes Research and Training Center,No.DK020593a VA MERIT Award,No.BX004845.
文摘Brain diseases affect 1 in 6 people worldwide.These diseases range from acute neurological conditions such as stroke to chronic neurodegenerative disorders such as Alzheimer’s disease.Recent advancements in tissue-engineered brain disease models have overcome many of the different shortcomings associated with the various animal models,tissue culture models,and epidemiologic patient data that are commonly used to study brain disease.One innovative method by which to model human neurological disease is via the directed differentiation of human pluripotent stem cells(hPSCs)to neural lineages including neurons,astrocytes,and oligodendrocytes.Three-dimensional models such as brain organoids have also been derived from hPSCs,offering more physiological relevance due to their incorporation of various cell types.As such,brain organoids can better model the pathophysiology of neural diseases observed in patients.In this review,we will emphasize recent developments in hPSC-based tissue culture models of neurological disorders and how they are being used to create neural disease models.