Reprogramming of somatic cells to induced pluripotent stem cells （iPSCs） is a comprehensive epigenetic process involving genome-wide modifications of histones and DNA methylation. This process is often incomplete, w...Reprogramming of somatic cells to induced pluripotent stem cells （iPSCs） is a comprehensive epigenetic process involving genome-wide modifications of histones and DNA methylation. This process is often incomplete, which subsequently affects iPSC reprograming, pluripotency, and differentiation capacity. Here, we review the epigenetic changes with a focus on histone modification （methylation and acetylation） and DNA modification （methylation） during iPSC induction. We look at changes in specific epigenetic signatures, aberrations and epigenetic memory during reprogramming and small molecules influencing the epigenetic reprogramming of somatic cells. Finally, we discuss how to improve iPSC generation and pluripotency through epigenetic manipulations.展开更多
Embryonic stem cells （ESCs） derived from the early embryos possess two important characteristics：self-renewal and pluripotency,which make ESCs ideal seed cells that could be potentially utilized for curing a number...Embryonic stem cells （ESCs） derived from the early embryos possess two important characteristics：self-renewal and pluripotency,which make ESCs ideal seed cells that could be potentially utilized for curing a number of degenerative and genetic diseases clinically.However,ethical concerns and immune rejection after cell transplantation limited the clinical application of ESCs.Fortunately,the recent advances in induced pluripotent stem cell （iPSC） research have clearly shown that differentiated somatic cells from various species could be reprogrammed into pluripotent state by ectopically expressing a combination of several transcription factors,which are highly enriched in ESCs.This ground-breaking achievement could circumvent most of the limitations that ESCs faced.However,it remains challenging if the iPS cell lines,especially the human iPSCs lines,available are fully pluripotent.Therefore,it is prerequisite to establish a molecular standard to distinguish the better quality iPSCs from the inferior ones.展开更多
MicroRNAs （miRNAs） are a class of small RNA molecules that are implicated in post-transcriptional reg- ulation of gene expression during development. The discovery and understanding of miRNAs has revolutionized the ...MicroRNAs （miRNAs） are a class of small RNA molecules that are implicated in post-transcriptional reg- ulation of gene expression during development. The discovery and understanding of miRNAs has revolutionized the traditional view of gene expression. Alport syndrome （AS） is an inherited disorder of type IV collagen, which most commonly leads to glomerulonephritis and kidney failure. Patients with AS inevitably reach end-stage renal disease and require renal replacement therapy, starting in young adulthood. In this study, Solexa sequencing was used to identify and quantitatively profile small RNAs from an AS family. We identified 30 known miRNAs that showed a sig- nificant change in expression between two individuals. Nineteen miRNAs were up-regulated and eleven were down-regulated. Forty-nine novel miRNAs showed significantly different levels of expression between two individuals. Gene target predictions for the miRNAs revealed that high ranking target genes were implicated in cell, cell part and cellular process categories. The purine metabolism pathway and mitogen-activated protein kinase （MAPK） signaling pathway were enriched by the largest number of target genes. These results strengthen the notion that miRNAs and their target genes are involved in AS and the data advance our understanding of miRNA function in the patho- genesis of AS.展开更多
Introducing a combination of transcription factors such as Oct4,Sox2,Klf4 and c-Myc（OSKM）enables reprogramming which converts somatic cells into induced pluripotent stem cells（i PSCs）（Takahashi and Yamanaka,2006...Introducing a combination of transcription factors such as Oct4,Sox2,Klf4 and c-Myc（OSKM）enables reprogramming which converts somatic cells into induced pluripotent stem cells（i PSCs）（Takahashi and Yamanaka,2006）.i PSCs play an important role in clinical and regenerative medicine because they can be utilized to model a specific disease or differentiate into functional cells for transplantation.Enhancing the efficiency of induction and improving the qualities of iPSCs are constant themes in this field.展开更多
Here we propose that the rejuvenation of leukocytes with iPSC technology in vitro and transfusion of cancer cellresistant white blood cells back to human body provide a prospective therapy for cancer patients.
Stem cell therapies show great potential for use in regenerative medicine, though advancements in safe stem cell technology need to be realized. Human induced pluripotent stem cells (hiPSCs) hold an advantage over oth...Stem cell therapies show great potential for use in regenerative medicine, though advancements in safe stem cell technology need to be realized. Human induced pluripotent stem cells (hiPSCs) hold an advantage over other stem cell types for use in cell-based therapies due to their potential as an unlimited source of rejuvenated and immunocompatible SCs which do not elicit the ethical and moral debates associated with the destruction of human embryos. Towards realization of this potential this review focuses on the recent progress in DNA-and xeno-free reprogramming methods, particularly small molecule methods, as well as addresses some of the latest insights on donor cell gene expression, telomere dynamics, and epigenetic aberrations that are a potential barrier to successful widespread clinical applications.展开更多
Alzheimer’s disease(AD)is a progressive neurodegenerative disorder characterized by massive neuronal loss in the brain.Both cortical glutamatergic neurons and basal forebrain cholinergic neurons(BFCNs)in the AD brain...Alzheimer’s disease(AD)is a progressive neurodegenerative disorder characterized by massive neuronal loss in the brain.Both cortical glutamatergic neurons and basal forebrain cholinergic neurons(BFCNs)in the AD brain are selectively vulnerable.The degeneration and dysfunction of these two subtypes of neurons are closely associated with the cognitive decline of AD patients.The determination of cellular and molecular mechanisms involved in AD pathogenesis,especially in the early stage,will largely facilitate the understanding of this disease and the develop-ment of proper intervention strategies.However,due to the inaccessibility of living neurons in the brains of patients,it remains unclear how cortical glutamatergic neurons and BFCNs respond to pathological stress in the early stage of AD.In this study,we established in vitro differentiation systems that can efficiently differentiate patient-derived iPSCs into BFCNs.We found that AD-BFCNs secreted less Aβpeptide than cortical glutamatergic neurons did,even though the Aβ42/Aβ40 ratio was comparable to that of cortical glutamatergic neurons.To further mimic the neuro-toxic niche in AD brain,we treated iPSC-derived neurons with Aβ42 oligomer(AβO).BFCNs are less sensitive to AβO induced tau phosphorylation and expression than cortical glutamatergic neurons.However,AβO could trigger apoptosis in both AD-cortical glutamatergic neurons and AD-BFCNs.In addition,AD iPSC-derived BFCNs and cortical glutamatergic neurons exhibited distinct electrophysiological firing patterns and elicited different responses to AβO treatment.These observations revealed that subtype-specific neurons display distinct neuropathological changes during the progression of AD,which might help to understand AD pathogenesis at the cellular level.展开更多
Major depressive disorder(MDD)is a debilitating psychiatric condition associated with substantial personal,societal,and economic costs.Despite considerable advances in research,most conventional antidepressant therapi...Major depressive disorder(MDD)is a debilitating psychiatric condition associated with substantial personal,societal,and economic costs.Despite considerable advances in research,most conventional antidepressant therapies fail to achieve adequate response in a significant proportion of patients,underscoring the need for novel,mechanism-based interventions.Lycium barbarum glycopeptide(LbGp),a bioactive compound with emerging neuroprotective properties,has been proposed as a candidate for antidepressant development;however,its therapeutic efficacy and underlying mechanisms remain largely uncharacterized.In this study,ventral forebrain organoids were generated from patients with MDD to investigate disease-related neurophysiological abnormalities.These organoids exhibited disrupted neuronal morphology,diminished calcium signaling,and impaired electrophysiological activity.Administration of LbGp effectively restored structural and functional deficits in MDD-derived organoids.Transcriptomic profiling revealed that LbGp ameliorated endoplasmic reticulum(ER)stress responses.To investigate the causative role of ER stress,control organoids were treated with the ER stress agonist CCT020312,which elicited neural activity impairments resembling those observed in MDD organoids.Notably,LbGp reversed the phenotypic consequences of CCT020312 exposure in control organoids.In conclusion,ventral forebrain organoids derived from individuals with MDD demonstrated that LbGp ameliorates disease-associated phenotypes by modulating ER stress.展开更多
Pluripotent stem cells(PSCs)are useful for developmental and translational research because they have the potential to differentiate into all cell types of an adult individual.Pigs are one of the most important domest...Pluripotent stem cells(PSCs)are useful for developmental and translational research because they have the potential to differentiate into all cell types of an adult individual.Pigs are one of the most important domestic ungulates,commonly used for food and as bioreactors.Generating stable pluripotent porcine PSC lines remains challenging.So far,the pluripotency gene network of porcine PSCs is poorly understood.Here we found that TBX3-derived induced pluripotent stem cells(iPSCs)closely resemble porcine 4-cell embryos with the capacity of totipotent-like stem cells(TLSCs).Interestingly,our data suggest that TBX3 facilitates the activation of H3K4me3 methyltransferase,specifically MLL1.Subsequent investigations revealed that the porcine 4-cell specific gene,MCL1,is a key downstream effector of the TBX3-MLL1 axis.Together,our study of the TBX3 regulatory network is helpful in the understanding of the totipotency characteristics of pigs.展开更多
基金supported by the Lundbeck Foundation(No.R151-2013-14439)the Danish Research Council for Independent Research(No.16942)
文摘Reprogramming of somatic cells to induced pluripotent stem cells （iPSCs） is a comprehensive epigenetic process involving genome-wide modifications of histones and DNA methylation. This process is often incomplete, which subsequently affects iPSC reprograming, pluripotency, and differentiation capacity. Here, we review the epigenetic changes with a focus on histone modification （methylation and acetylation） and DNA modification （methylation） during iPSC induction. We look at changes in specific epigenetic signatures, aberrations and epigenetic memory during reprogramming and small molecules influencing the epigenetic reprogramming of somatic cells. Finally, we discuss how to improve iPSC generation and pluripotency through epigenetic manipulations.
基金supported by the grants from the Ministry of Science and Technology of China (Nos 2008AA022311,2010CB944900 and 2008AA1011005)
文摘Embryonic stem cells （ESCs） derived from the early embryos possess two important characteristics：self-renewal and pluripotency,which make ESCs ideal seed cells that could be potentially utilized for curing a number of degenerative and genetic diseases clinically.However,ethical concerns and immune rejection after cell transplantation limited the clinical application of ESCs.Fortunately,the recent advances in induced pluripotent stem cell （iPSC） research have clearly shown that differentiated somatic cells from various species could be reprogrammed into pluripotent state by ectopically expressing a combination of several transcription factors,which are highly enriched in ESCs.This ground-breaking achievement could circumvent most of the limitations that ESCs faced.However,it remains challenging if the iPS cell lines,especially the human iPSCs lines,available are fully pluripotent.Therefore,it is prerequisite to establish a molecular standard to distinguish the better quality iPSCs from the inferior ones.
基金supported by the Shenzhen Knowledge Innovation Program of Basic Research Items of Guangdong Province(No.JCYJ2014 0416122812045),China
文摘MicroRNAs （miRNAs） are a class of small RNA molecules that are implicated in post-transcriptional reg- ulation of gene expression during development. The discovery and understanding of miRNAs has revolutionized the traditional view of gene expression. Alport syndrome （AS） is an inherited disorder of type IV collagen, which most commonly leads to glomerulonephritis and kidney failure. Patients with AS inevitably reach end-stage renal disease and require renal replacement therapy, starting in young adulthood. In this study, Solexa sequencing was used to identify and quantitatively profile small RNAs from an AS family. We identified 30 known miRNAs that showed a sig- nificant change in expression between two individuals. Nineteen miRNAs were up-regulated and eleven were down-regulated. Forty-nine novel miRNAs showed significantly different levels of expression between two individuals. Gene target predictions for the miRNAs revealed that high ranking target genes were implicated in cell, cell part and cellular process categories. The purine metabolism pathway and mitogen-activated protein kinase （MAPK） signaling pathway were enriched by the largest number of target genes. These results strengthen the notion that miRNAs and their target genes are involved in AS and the data advance our understanding of miRNA function in the patho- genesis of AS.
基金supported by the Strategic Priority Research Program of Chinese Academy of Sciences (No. XDA01020102)the grant from the Natural Science Foundation of China (No. 81225004)
文摘Introducing a combination of transcription factors such as Oct4,Sox2,Klf4 and c-Myc（OSKM）enables reprogramming which converts somatic cells into induced pluripotent stem cells（i PSCs）（Takahashi and Yamanaka,2006）.i PSCs play an important role in clinical and regenerative medicine because they can be utilized to model a specific disease or differentiate into functional cells for transplantation.Enhancing the efficiency of induction and improving the qualities of iPSCs are constant themes in this field.
文摘Here we propose that the rejuvenation of leukocytes with iPSC technology in vitro and transfusion of cancer cellresistant white blood cells back to human body provide a prospective therapy for cancer patients.
文摘Stem cell therapies show great potential for use in regenerative medicine, though advancements in safe stem cell technology need to be realized. Human induced pluripotent stem cells (hiPSCs) hold an advantage over other stem cell types for use in cell-based therapies due to their potential as an unlimited source of rejuvenated and immunocompatible SCs which do not elicit the ethical and moral debates associated with the destruction of human embryos. Towards realization of this potential this review focuses on the recent progress in DNA-and xeno-free reprogramming methods, particularly small molecule methods, as well as addresses some of the latest insights on donor cell gene expression, telomere dynamics, and epigenetic aberrations that are a potential barrier to successful widespread clinical applications.
基金National Key Basic Research and Development Program of China(2019YFA0801402,2018YFA0800100,2018YFA0107200,2018YFA0801402)Major Project of Guangzhou National Laboratory(GZNL2023A02005)+1 种基金Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16020501,XDA16020404)National Natural Science Foundation of China(31800854,32130030,31900454)。
文摘Alzheimer’s disease(AD)is a progressive neurodegenerative disorder characterized by massive neuronal loss in the brain.Both cortical glutamatergic neurons and basal forebrain cholinergic neurons(BFCNs)in the AD brain are selectively vulnerable.The degeneration and dysfunction of these two subtypes of neurons are closely associated with the cognitive decline of AD patients.The determination of cellular and molecular mechanisms involved in AD pathogenesis,especially in the early stage,will largely facilitate the understanding of this disease and the develop-ment of proper intervention strategies.However,due to the inaccessibility of living neurons in the brains of patients,it remains unclear how cortical glutamatergic neurons and BFCNs respond to pathological stress in the early stage of AD.In this study,we established in vitro differentiation systems that can efficiently differentiate patient-derived iPSCs into BFCNs.We found that AD-BFCNs secreted less Aβpeptide than cortical glutamatergic neurons did,even though the Aβ42/Aβ40 ratio was comparable to that of cortical glutamatergic neurons.To further mimic the neuro-toxic niche in AD brain,we treated iPSC-derived neurons with Aβ42 oligomer(AβO).BFCNs are less sensitive to AβO induced tau phosphorylation and expression than cortical glutamatergic neurons.However,AβO could trigger apoptosis in both AD-cortical glutamatergic neurons and AD-BFCNs.In addition,AD iPSC-derived BFCNs and cortical glutamatergic neurons exhibited distinct electrophysiological firing patterns and elicited different responses to AβO treatment.These observations revealed that subtype-specific neurons display distinct neuropathological changes during the progression of AD,which might help to understand AD pathogenesis at the cellular level.
基金supported by the National Key Research and Development Program of China(2021YFA1101800,2022YFA1104800,2023YFF1203600)National Natural Science Foundation of China(82325015,82171528,U23A20429,82371260,21904069,22274079,82401794)+2 种基金Jiangsu Provincial Natural Science Fund for Excellent Young Scholars(BK20240131)Natural Science Foundation of Jiangsu Province(BK20200677)Joint Project of the Yangtze River Delta Science and Technology Innovation Community(2024CSJZN0600)。
文摘Major depressive disorder(MDD)is a debilitating psychiatric condition associated with substantial personal,societal,and economic costs.Despite considerable advances in research,most conventional antidepressant therapies fail to achieve adequate response in a significant proportion of patients,underscoring the need for novel,mechanism-based interventions.Lycium barbarum glycopeptide(LbGp),a bioactive compound with emerging neuroprotective properties,has been proposed as a candidate for antidepressant development;however,its therapeutic efficacy and underlying mechanisms remain largely uncharacterized.In this study,ventral forebrain organoids were generated from patients with MDD to investigate disease-related neurophysiological abnormalities.These organoids exhibited disrupted neuronal morphology,diminished calcium signaling,and impaired electrophysiological activity.Administration of LbGp effectively restored structural and functional deficits in MDD-derived organoids.Transcriptomic profiling revealed that LbGp ameliorated endoplasmic reticulum(ER)stress responses.To investigate the causative role of ER stress,control organoids were treated with the ER stress agonist CCT020312,which elicited neural activity impairments resembling those observed in MDD organoids.Notably,LbGp reversed the phenotypic consequences of CCT020312 exposure in control organoids.In conclusion,ventral forebrain organoids derived from individuals with MDD demonstrated that LbGp ameliorates disease-associated phenotypes by modulating ER stress.
基金funded by the National Basic Research Program of China(2022YFD1302200,2023YFF1000904,2023ZD0404303 and 2021YFD1200301)the National Natural Science Foundation of China(32072806,32372970 and 32002246)+2 种基金the Program of Shaanxi Province Science and Technology Innovation Team,China(2019TD-036)the Key Technologies Demonstration of Animal Husbandry in Shaanxi Province,China(20221086 and 20230978)the Inner Mongolia Autonomous Region Open Competition Project,China(2022JBGS0025).
文摘Pluripotent stem cells(PSCs)are useful for developmental and translational research because they have the potential to differentiate into all cell types of an adult individual.Pigs are one of the most important domestic ungulates,commonly used for food and as bioreactors.Generating stable pluripotent porcine PSC lines remains challenging.So far,the pluripotency gene network of porcine PSCs is poorly understood.Here we found that TBX3-derived induced pluripotent stem cells(iPSCs)closely resemble porcine 4-cell embryos with the capacity of totipotent-like stem cells(TLSCs).Interestingly,our data suggest that TBX3 facilitates the activation of H3K4me3 methyltransferase,specifically MLL1.Subsequent investigations revealed that the porcine 4-cell specific gene,MCL1,is a key downstream effector of the TBX3-MLL1 axis.Together,our study of the TBX3 regulatory network is helpful in the understanding of the totipotency characteristics of pigs.
