Three-dimensional cultured organoids have become a powerful in vitro research tool that preserves genetic,phenotypic and behavioral trait of in vivo organs,which can be established from both pluripotent stem cells and...Three-dimensional cultured organoids have become a powerful in vitro research tool that preserves genetic,phenotypic and behavioral trait of in vivo organs,which can be established from both pluripotent stem cells and adult stem cells.Organoids derived from adult stem cells can be established directly from diseased epithelium and matched normal tissues,and organoids can also be genetically manipulated by CRISPR-Cas9 technology.Applications of organoids in basic research involve the modeling of human development and diseases,including genetic,infectious and malignant diseases.Importantly,accumulating evidence suggests that biobanks of patientderived organoids for many cancers and cystic fibrosis have great value for drug development and personalized medicine.In addition,organoids hold promise for regenerative medicine.In the present review,we discuss the applications of organoids in the basic and translational research.展开更多
Three-dimensional(3D)culture systems are becoming increasingly popular due to their ability to mimic tissue-like structures more effectively than the monolayer cultures.In cancer and stem cell research,the natural cel...Three-dimensional(3D)culture systems are becoming increasingly popular due to their ability to mimic tissue-like structures more effectively than the monolayer cultures.In cancer and stem cell research,the natural cell characteristics and architectures are closely mimicked by the 3D cell models.Thus,the 3D cell cultures are promising and suitable systems for various proposes,ranging from disease modeling to drug target identification as well as potential therapeutic substances that may transform our lives.This review provides a comprehensive compendium of recent advancements in culturing cells,in particular cancer and stem cells,using 3D culture techniques.The major approaches highlighted here include cell spheroids,hydrogel embedding,bioreactors,scaffolds,and bioprinting.In addition,the progress of employing 3D cell culture systems as a platform for cancer and stem cell research was addressed,and the prominent studies of 3D cell culture systems were discussed.展开更多
Human pluripotent stem cell(hPSC)-derived kidney organoids share similarities with the fetal kidney.However,the current hPSC-derived kidney organoids have some limitations,including the inability to perform nephrogene...Human pluripotent stem cell(hPSC)-derived kidney organoids share similarities with the fetal kidney.However,the current hPSC-derived kidney organoids have some limitations,including the inability to perform nephrogenesis and lack of a corticomedullary definition,uniform vascular system,and coordinated exit path-way for urinary filtrate.Therefore,further studies are required to produce hPSC-derived kidney organoids that accurately mimic human kidneys to facilitate research on kidney development,regeneration,disease modeling,and drug screening.In this review,we discussed recent advances in the generation of hPSC-derived kidney organoids,how these organoids contribute to the understanding of human kidney development and research in disease modeling.Additionally,the limitations,future research focus,and applications of hPSC-derived kidney organoids were highlighted.展开更多
Several diseases have been successfully modeled since the development of induced pluripotent stem cell(i PSC) technology in 2006. Since then, methods for increased reprogramming efficiency and cell culture maintenance...Several diseases have been successfully modeled since the development of induced pluripotent stem cell(i PSC) technology in 2006. Since then, methods for increased reprogramming efficiency and cell culture maintenance have been optimized and many protocols for differentiating stem cell lines have been successfully developed, allowing the generation of several cellular subtypes in vitro. Gene editing technologies have also greatly advanced lately, enhancing disease-specific phenotypes by creating isogenic cell lines, allowing mutations to be corrected in affected samples or inserted in control lines. Neurological disorders have benefited the most from i PSC-disease modeling for its capability for generating disease-relevant cell types in vitro from the central nervous system, such as neurons and glial cells, otherwise only available from post-mortem samples. Patient-specific i PSC-derived neural cells can recapitulate the phenotypes of these diseases and therefore, considerably enrich our understanding of pathogenesis, disease mechanism and facilitate the development of drug screening platforms for novel therapeutic targets. Here, we review the accomplishments and the current progress in human neurological disorders by using i PSC modeling for Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal muscular atrophy, amyotrophic lateral sclerosis, duchenne muscular dystrophy, schizophrenia and autism spectrum disorders, which include Timothy syndrome, Fragile X syndrome, Angelman syndrome, Prader-Willi syndrome, PhelanMc Dermid, Rett syndrome as well as Nonsyndromic Autism.展开更多
Amyotrophic lateral sclerosis（ALS） and motor neuron diseases（MNDs） are progressive neurodegenerative diseases that affect nerve cells in the brain affecting upper and lower motor neurons（UMNs/LMNs）, brain stem a...Amyotrophic lateral sclerosis（ALS） and motor neuron diseases（MNDs） are progressive neurodegenerative diseases that affect nerve cells in the brain affecting upper and lower motor neurons（UMNs/LMNs）, brain stem and spinal cord. The clinical phenotype is characterized by loss of motor neurons（MNs）, muscular weakness and atrophy eventually leading to paralysis and death due to respiratory failure within 3–5 years after disease onset. No effective treatment or cure is currently available that halts or reverses ALS and MND except FDA approved drug riluzole that only modestly slows the progression of ALS in some patients. Recent advances in human derived induced pluripotent stem cells have made it possible for the first time to obtain substantial amounts of human cells to recapitulate in vitro “disease in dish” and test some of the underlying pathogenetic mechanisms involved in ALS and MNDs. In this review, I discussed the opportunities and challenges of induced pluropotent stem cells-derived motor neurons for treatment of ALS and MND patients with special emphasis on their implications in finding a cure for ALS and MNDs.展开更多
Chronic infection with hepatitis B virus(HBV)remains a global health concern despite the availability of vaccines.To date,the development of effective treatments has been severely hampered by the lack of reliable,repr...Chronic infection with hepatitis B virus(HBV)remains a global health concern despite the availability of vaccines.To date,the development of effective treatments has been severely hampered by the lack of reliable,reproducible,and scalable in vitro modeling systems that precisely recapitulate the virus life cycle and represent virus-host interactions.With the progressive understanding of liver organogenesis mechanisms,the development of human induced pluripotent stem cell(iPSC)-derived hepatic sources and stromal cellular compositions provides novel strategies for personalized modeling and treatment of liver disease.Further,advancements in three-dimensional culture of self-organized liver-like organoids considerably promote in vitro modeling of intact human liver tissue,in terms of both hepatic function and other physiological characteristics.Combined with our experiences in the investigation of HBV infections using liver organoids,we have summarized the advances in modeling reported thus far and discussed the limitations and ongoing challenges in the application of liver organoids,particularly those with multi-cellular components derived from human iPSCs.This review provides general guidelines for establishing clinical-grade iPSC-derived multi-cellular organoids in modeling personalized hepatitis virus infection and other liver diseases,as well as drug testing and transplantation therapy.展开更多
Recent advances in the study of human hepatocytes derived from induced pluripotent stem cells(iPSC)represent new promises for liver disease study and drug discovery.Human hepatocytes or hepatocyte-like cells different...Recent advances in the study of human hepatocytes derived from induced pluripotent stem cells(iPSC)represent new promises for liver disease study and drug discovery.Human hepatocytes or hepatocyte-like cells differentiated from iPSC recapitulate many func-tional properties of primary human hepatocytes and have been demonstrated as a powerful and efficient tool to model human liver metabolic diseases and fa-cilitate drug development process.In this review,we summarize the recent progress in this field and discuss the future perspective of the application of human iPSC derived hepatocytes.展开更多
The somatic epigenome can be reprogrammed to a pluri-potent state by a combination of transcription factors.Altering cell fate involves transcription factors coopera-tion,epigenetic reconfi guration,such as DNA methyl...The somatic epigenome can be reprogrammed to a pluri-potent state by a combination of transcription factors.Altering cell fate involves transcription factors coopera-tion,epigenetic reconfi guration,such as DNA methylation and histone modification,posttranscriptional regulation by microRNAs,and so on.Nevertheless,such reprogram-ming is inefficient.Evidence suggests that during the early stage of reprogramming,the process is stochastic,but by the late stage,it is deterministic.In addition to con-ventional reprogramming methods,dozens of small mol-ecules have been identifi ed that can functionally replace reprogramming factors and signifi cantly improve induced pluripotent stem cell(iPSC)reprogramming.Indeed,iPS cells have been created recently using chemical com-pounds only.iPSCs are thought to display subtle genetic and epigenetic variability;this variability is not random,but occurs at hotspots across the genome.Here we dis-cuss the progress and current perspectives in the fi eld.Research into the reprogramming process today will pave the way for great advances in regenerative medicine in the future.展开更多
Mice have frequently been used to model human diseases involving immune dysregulation such as autoimmune and inflammatory diseases.These models help elucidatethe mechanisms underlying the disease and in the developmen...Mice have frequently been used to model human diseases involving immune dysregulation such as autoimmune and inflammatory diseases.These models help elucidatethe mechanisms underlying the disease and in the development of novel therapies.However,if mice are deficient in certain cells and/or effectors associated with human diseases,how can their functions be investigated in this species?Mucosal-associated invariant T(MAIT)cells,a novel innate-like T cell family member,are a good example.MAIT cells are abundant in humans but scarce in laboratory mice.MAIT cells harbor an invariant T cell receptor and recognize nonpeptidic antigens vitamin B2metabolites from bacteria and yeasts.Recent studies have shown that MAIT cells play a pivotal role in human diseases such as bacterial infections and autoimmune and inflammatory diseases.MAIT cells possess granulysin,a human-specific effector molecule,but granulysin and its homologue are absent in mice.Furthermore,MAIT cells show poor proliferation in vitro.To overcome these problems and further our knowledge of MAIT cells,we have established a method to expand MAIT cells via induced pluripotent stem cells(iP SCs).In this review,we describe recent advances in the field of MAIT cell research and our approach for human disease modeling with iP SCderived MAIT cells.展开更多
基金This work was supported by the National Natural Science Foundation of China(31470826,31670858,and 81773357 to Hua)Shanghai Sailing Program(19YF1409500 to Li)Shanghai Anticancer Association EYAS PROJECT(SACA-CY1A05 to Li).
文摘Three-dimensional cultured organoids have become a powerful in vitro research tool that preserves genetic,phenotypic and behavioral trait of in vivo organs,which can be established from both pluripotent stem cells and adult stem cells.Organoids derived from adult stem cells can be established directly from diseased epithelium and matched normal tissues,and organoids can also be genetically manipulated by CRISPR-Cas9 technology.Applications of organoids in basic research involve the modeling of human development and diseases,including genetic,infectious and malignant diseases.Importantly,accumulating evidence suggests that biobanks of patientderived organoids for many cancers and cystic fibrosis have great value for drug development and personalized medicine.In addition,organoids hold promise for regenerative medicine.In the present review,we discuss the applications of organoids in the basic and translational research.
文摘Three-dimensional(3D)culture systems are becoming increasingly popular due to their ability to mimic tissue-like structures more effectively than the monolayer cultures.In cancer and stem cell research,the natural cell characteristics and architectures are closely mimicked by the 3D cell models.Thus,the 3D cell cultures are promising and suitable systems for various proposes,ranging from disease modeling to drug target identification as well as potential therapeutic substances that may transform our lives.This review provides a comprehensive compendium of recent advancements in culturing cells,in particular cancer and stem cells,using 3D culture techniques.The major approaches highlighted here include cell spheroids,hydrogel embedding,bioreactors,scaffolds,and bioprinting.In addition,the progress of employing 3D cell culture systems as a platform for cancer and stem cell research was addressed,and the prominent studies of 3D cell culture systems were discussed.
基金the National Natural Science Foundation of China,No.82360148Guizhou Science&Technology Department,No.QKHPTRC2018-5636-2 and No.QKHPTRC2020-2201.
文摘Human pluripotent stem cell(hPSC)-derived kidney organoids share similarities with the fetal kidney.However,the current hPSC-derived kidney organoids have some limitations,including the inability to perform nephrogenesis and lack of a corticomedullary definition,uniform vascular system,and coordinated exit path-way for urinary filtrate.Therefore,further studies are required to produce hPSC-derived kidney organoids that accurately mimic human kidneys to facilitate research on kidney development,regeneration,disease modeling,and drug screening.In this review,we discussed recent advances in the generation of hPSC-derived kidney organoids,how these organoids contribute to the understanding of human kidney development and research in disease modeling.Additionally,the limitations,future research focus,and applications of hPSC-derived kidney organoids were highlighted.
文摘Several diseases have been successfully modeled since the development of induced pluripotent stem cell(i PSC) technology in 2006. Since then, methods for increased reprogramming efficiency and cell culture maintenance have been optimized and many protocols for differentiating stem cell lines have been successfully developed, allowing the generation of several cellular subtypes in vitro. Gene editing technologies have also greatly advanced lately, enhancing disease-specific phenotypes by creating isogenic cell lines, allowing mutations to be corrected in affected samples or inserted in control lines. Neurological disorders have benefited the most from i PSC-disease modeling for its capability for generating disease-relevant cell types in vitro from the central nervous system, such as neurons and glial cells, otherwise only available from post-mortem samples. Patient-specific i PSC-derived neural cells can recapitulate the phenotypes of these diseases and therefore, considerably enrich our understanding of pathogenesis, disease mechanism and facilitate the development of drug screening platforms for novel therapeutic targets. Here, we review the accomplishments and the current progress in human neurological disorders by using i PSC modeling for Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal muscular atrophy, amyotrophic lateral sclerosis, duchenne muscular dystrophy, schizophrenia and autism spectrum disorders, which include Timothy syndrome, Fragile X syndrome, Angelman syndrome, Prader-Willi syndrome, PhelanMc Dermid, Rett syndrome as well as Nonsyndromic Autism.
文摘Amyotrophic lateral sclerosis（ALS） and motor neuron diseases（MNDs） are progressive neurodegenerative diseases that affect nerve cells in the brain affecting upper and lower motor neurons（UMNs/LMNs）, brain stem and spinal cord. The clinical phenotype is characterized by loss of motor neurons（MNs）, muscular weakness and atrophy eventually leading to paralysis and death due to respiratory failure within 3–5 years after disease onset. No effective treatment or cure is currently available that halts or reverses ALS and MND except FDA approved drug riluzole that only modestly slows the progression of ALS in some patients. Recent advances in human derived induced pluripotent stem cells have made it possible for the first time to obtain substantial amounts of human cells to recapitulate in vitro “disease in dish” and test some of the underlying pathogenetic mechanisms involved in ALS and MNDs. In this review, I discussed the opportunities and challenges of induced pluropotent stem cells-derived motor neurons for treatment of ALS and MND patients with special emphasis on their implications in finding a cure for ALS and MNDs.
基金Supported by National Natural Science Foundation of China,No.82070638 and No.81770621JSPS KAKENHI,No.JP18H02866.
文摘Chronic infection with hepatitis B virus(HBV)remains a global health concern despite the availability of vaccines.To date,the development of effective treatments has been severely hampered by the lack of reliable,reproducible,and scalable in vitro modeling systems that precisely recapitulate the virus life cycle and represent virus-host interactions.With the progressive understanding of liver organogenesis mechanisms,the development of human induced pluripotent stem cell(iPSC)-derived hepatic sources and stromal cellular compositions provides novel strategies for personalized modeling and treatment of liver disease.Further,advancements in three-dimensional culture of self-organized liver-like organoids considerably promote in vitro modeling of intact human liver tissue,in terms of both hepatic function and other physiological characteristics.Combined with our experiences in the investigation of HBV infections using liver organoids,we have summarized the advances in modeling reported thus far and discussed the limitations and ongoing challenges in the application of liver organoids,particularly those with multi-cellular components derived from human iPSCs.This review provides general guidelines for establishing clinical-grade iPSC-derived multi-cellular organoids in modeling personalized hepatitis virus infection and other liver diseases,as well as drug testing and transplantation therapy.
基金supported by Sanofi-Aventis,The Helmsley Charitable Trust and The Ellison Medical Foundation.GHL was supported by 100 Talents Program of the Chinese Academy of Sciences.
文摘Recent advances in the study of human hepatocytes derived from induced pluripotent stem cells(iPSC)represent new promises for liver disease study and drug discovery.Human hepatocytes or hepatocyte-like cells differentiated from iPSC recapitulate many func-tional properties of primary human hepatocytes and have been demonstrated as a powerful and efficient tool to model human liver metabolic diseases and fa-cilitate drug development process.In this review,we summarize the recent progress in this field and discuss the future perspective of the application of human iPSC derived hepatocytes.
基金the National Institutes of Health(NS079625 and HD073162 to P.J.).
文摘The somatic epigenome can be reprogrammed to a pluri-potent state by a combination of transcription factors.Altering cell fate involves transcription factors coopera-tion,epigenetic reconfi guration,such as DNA methylation and histone modification,posttranscriptional regulation by microRNAs,and so on.Nevertheless,such reprogram-ming is inefficient.Evidence suggests that during the early stage of reprogramming,the process is stochastic,but by the late stage,it is deterministic.In addition to con-ventional reprogramming methods,dozens of small mol-ecules have been identifi ed that can functionally replace reprogramming factors and signifi cantly improve induced pluripotent stem cell(iPSC)reprogramming.Indeed,iPS cells have been created recently using chemical com-pounds only.iPSCs are thought to display subtle genetic and epigenetic variability;this variability is not random,but occurs at hotspots across the genome.Here we dis-cuss the progress and current perspectives in the fi eld.Research into the reprogramming process today will pave the way for great advances in regenerative medicine in the future.
文摘Mice have frequently been used to model human diseases involving immune dysregulation such as autoimmune and inflammatory diseases.These models help elucidatethe mechanisms underlying the disease and in the development of novel therapies.However,if mice are deficient in certain cells and/or effectors associated with human diseases,how can their functions be investigated in this species?Mucosal-associated invariant T(MAIT)cells,a novel innate-like T cell family member,are a good example.MAIT cells are abundant in humans but scarce in laboratory mice.MAIT cells harbor an invariant T cell receptor and recognize nonpeptidic antigens vitamin B2metabolites from bacteria and yeasts.Recent studies have shown that MAIT cells play a pivotal role in human diseases such as bacterial infections and autoimmune and inflammatory diseases.MAIT cells possess granulysin,a human-specific effector molecule,but granulysin and its homologue are absent in mice.Furthermore,MAIT cells show poor proliferation in vitro.To overcome these problems and further our knowledge of MAIT cells,we have established a method to expand MAIT cells via induced pluripotent stem cells(iP SCs).In this review,we describe recent advances in the field of MAIT cell research and our approach for human disease modeling with iP SCderived MAIT cells.
