We have previously shown the neuroprotective and pro-neurogenic activity of microneurotrophin BNN-20 in the substantia nigra of the“weaver”mouse,a model of progressive nigrostriatal degeneration.Here,we extended our...We have previously shown the neuroprotective and pro-neurogenic activity of microneurotrophin BNN-20 in the substantia nigra of the“weaver”mouse,a model of progressive nigrostriatal degeneration.Here,we extended our investigation in two clinically-relevant ways.First,we assessed the effects of BNN-20 on human induced pluripotent stem cell-derived neural progenitor cells and neurons derived from healthy and parkinsonian donors.Second,we assessed if BNN-20 can boost the outcome of mouse neural progenitor cell intranigral transplantations in weaver mice,at late stages of degeneration.We found that BNN-20 has limited direct effects on cultured human induced pluripotent stem cell-derived neural progenitor cells,marginally enhancing their differentiation towards neurons and partially reversing the pathological phenotype of dopaminergic neurons generated from parkinsonian donors.In agreement,we found no effects of BNN-20 on the mouse neural progenitor cells grafted in the substantia nigra of weaver mice.However,the graft strongly induced an endogenous neurogenic response throughout the midbrain,which was significantly enhanced by the administration of microneurotrophin BNN-20.Our results provide straightforward evidence of the existence of an endogenous midbrain neurogenic system that can be specifically strengthened by BNN-20.Interestingly,the lack of major similar activity on cultured human induced pluripotent stem cell-derived neural progenitors and their progeny reveals the in vivo specificity of the aforementioned pro-neurogenic effect.展开更多
The local microenvironment is essential to stem cell-based therapy for ischemic stroke,and spatiotemporal changes of the microenvironment in the pathological process provide vital clues for understanding the therapeut...The local microenvironment is essential to stem cell-based therapy for ischemic stroke,and spatiotemporal changes of the microenvironment in the pathological process provide vital clues for understanding the therapeutic mechanisms.However,relevant studies on microenvironmental changes were mainly confined in the acute phase of stroke,and long-term changes remain unclear.This study aimed to investigate the microenvironmental changes in the subacute and chronic phases of ischemic stroke after stem cell transplantation.Herein,induced pluripotent stem cells(iPSCs)and neural stem cells(NSCs)were transplanted into the ischemic brain established by middle cerebral artery occlusion surgery.Positron emission tomography imaging and neurological tests were applied to evaluate the metabolic and neurofunctional alterations of rats transplanted with stem cells.Quantitative proteomics was employed to investigate the protein expression profiles in iPSCs-transplanted brain in the subacute and chronic phases of stroke.Compared with NSCs-transplanted rats,significantly increased glucose metabolism and neurofunctional scores were observed in iPSCs-transplanted rats.Subsequent proteomic data of iPSCs-transplanted rats identified a total of 39 differentially expressed proteins in the subacute and chronic phases,which are involved in various ischemic stroke-related biological processes,including neuronal survival,axonal remodeling,antioxidative stress,and mitochondrial function restoration.Taken together,our study indicated that iPSCs have a positive therapeutic effect in ischemic stroke and emphasized the wide-ranging microenvironmental changes in the subacute and chronic phases.展开更多
Human embryonic stem cells(hESCs)are pluripotent cells that have the ability of unlimited self-renewal and can be differentiated into different cell lineages,includ-ing neural stem(NS)cells.Diverse regulatory signalin...Human embryonic stem cells(hESCs)are pluripotent cells that have the ability of unlimited self-renewal and can be differentiated into different cell lineages,includ-ing neural stem(NS)cells.Diverse regulatory signaling pathways of neural stem cells differentiation have been discovered,and this will be of great benefit to uncover the mechanisms of neuronal differentiation in vivo and in vitro.However,the limitations of hESCs resource along with the religious and ethical concerns impede the pro-gress of ESCs application.Therefore,the induced pluri-potent stem cells(iPSCs)via somatic cell reprogramming have opened up another new territory for regenerative medicine.iPSCs now can be derived from a number of lin-eages of cells,and are able to differentiate into certain cell types,including neurons.Patient-specifi c iPSCs are being used in human neurodegenerative disease modeling and drug screening.Furthermore,with the development of somatic direct reprogramming or lineage reprogramming technique,a more effective approach for regenerative medicine could become a complement for iPSCs.展开更多
In 2006,Takahashi and Yamanaka first created induced pluripotent stem cells from mouse fibroblasts via the retroviral introduction of genes encoding the transcription factors Oct3/4,Sox2,Klf44,and c-Myc.Since then,the...In 2006,Takahashi and Yamanaka first created induced pluripotent stem cells from mouse fibroblasts via the retroviral introduction of genes encoding the transcription factors Oct3/4,Sox2,Klf44,and c-Myc.Since then,the future clinical application of somatic cell reprogramming technology has become an attractive research topic in the field of regenerative medicine.Of note,considerable interest has been placed in circumventing ethical issues linked to embryonic stem cell research.However,tumorigenicity,immunogenicity,and heterogeneity may hamper attempts to deploy this technology therapeutically.This review highlights the progress aimed at reducing induced pluripotent stem cells tumorigenicity risk and howto assess the safety of induced pluripotent stem cells cell therapy products.展开更多
The purpose of this study was to primarily culture human periodontal ligament cells(hPDLCs)and to reprogram hPDLCs with exogenous genes via a lentivirus-mediated transfection system.Then induced pluripotent stem cells...The purpose of this study was to primarily culture human periodontal ligament cells(hPDLCs)and to reprogram hPDLCs with exogenous genes via a lentivirus-mediated transfection system.Then induced pluripotent stem cells derived from h PDLCs(hPDLC-iPSCs)were identified.Alizarin red staining was used to observe the formation of mineralized nodules and real-time Polymerase Chain Reaction(PCR)was used to detect the expression of osteogenic genes.For the in vivo experiment,nude mouse skull defect models were established and cell sheets were made to repair the bone defect.The reprogrammed cells were positive for alkaline phosphatase(ALP)staining and embryonic stem cells(ESCs)-specific proteins,and could form teratomas.After osteogenic induction,alizarin red staining showed that the number of mineralized nodules in the h PDLC-i PSCs group was more and the osteogenic related factors ALP,osteocalcin(OCN),Col-I and Runx2 were also expressed higher in hPDLC-iPSCs.The hPDLC-iPSC cell sheets were all successfully made.Histological analysis showed that the h PDLC-i PSC cell sheet got new bone formation.These results demonstrated that hPDLC-iPSCs were successfully generated from human periodontal ligament fibroblasts and hPDLC-iPSC cell sheets provided new options for bone tissue engineering.展开更多
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
Progress of cell therapy for muscular dystrophies is slow. Although there are clinical trials of myoblast delivery, the result is not satisfactory. However, human stem cell especially induced pluripotent stem cells （...Progress of cell therapy for muscular dystrophies is slow. Although there are clinical trials of myoblast delivery, the result is not satisfactory. However, human stem cell especially induced pluripotent stem cells （iPSCs） could overcome the problem by successful differentiation. Generally speaking, there are two strategies for that goal one is by plasmid and the other is by differentiation factors in vitro. This review covers recent advances in the differentiation field of human embryonic stem cells （ESCs） and iPSCs, showing different differentiation methods as a potential therapy way.展开更多
The stem cells of an organism only possess extraordinary capacity to change into different cell types during the early life and growth of an organism. When these stem cells divide into different new cells, these eithe...The stem cells of an organism only possess extraordinary capacity to change into different cell types during the early life and growth of an organism. When these stem cells divide into different new cells, these either remain as stem cells or develop to become other cells with specialized function. For this reason, stem cells offer direct relevance to human health, as theoretically, using stem cell technology, different organs are expected to be regenerated. To this, the Human Embryonic Stem Cells (HESCs) are natural pluripotent cell, but ethical issues covering many countries have put research work on a bit back-foot. However, the Induced Pluripotent Stem Cells (iPSCs) technology has completely revitalized the world to use this technology universally and it therefore seems that more research on this technology will surely be of enormous help in public health. In addition, application of the stem cell technology in personalized-medicine has been started recently. In this concern, the stem cell banking facilities have provided new avenues for preserving the cord blood of the new-borne child and treat them in future by using her/his own preserved stem cells. However, like all new technologies, the output from stem cell research requires to be evaluated more closely. Furthermore, with proper guidelines on ethical issues and extended research following these strategies, the stem cell technology is expected to not only be of huge benefit to human health, but also the benefit can be extended to the survival of endangered animals as well.展开更多
基金co-financed by Greece and the European Union(European Social Fund-ESF)through the Operational Programme《Human Resources Development,Education and Lifelong Learning 2014–2020》in the context of the project“NeuroProPar”(MIS 5047138,to IK)。
文摘We have previously shown the neuroprotective and pro-neurogenic activity of microneurotrophin BNN-20 in the substantia nigra of the“weaver”mouse,a model of progressive nigrostriatal degeneration.Here,we extended our investigation in two clinically-relevant ways.First,we assessed the effects of BNN-20 on human induced pluripotent stem cell-derived neural progenitor cells and neurons derived from healthy and parkinsonian donors.Second,we assessed if BNN-20 can boost the outcome of mouse neural progenitor cell intranigral transplantations in weaver mice,at late stages of degeneration.We found that BNN-20 has limited direct effects on cultured human induced pluripotent stem cell-derived neural progenitor cells,marginally enhancing their differentiation towards neurons and partially reversing the pathological phenotype of dopaminergic neurons generated from parkinsonian donors.In agreement,we found no effects of BNN-20 on the mouse neural progenitor cells grafted in the substantia nigra of weaver mice.However,the graft strongly induced an endogenous neurogenic response throughout the midbrain,which was significantly enhanced by the administration of microneurotrophin BNN-20.Our results provide straightforward evidence of the existence of an endogenous midbrain neurogenic system that can be specifically strengthened by BNN-20.Interestingly,the lack of major similar activity on cultured human induced pluripotent stem cell-derived neural progenitors and their progeny reveals the in vivo specificity of the aforementioned pro-neurogenic effect.
基金sponsored by the National Key Research and Development Program of China(No.2016YFA0100-900)and the Fund for Shanxi“1331 Project Key Innovative Research Team.
文摘The local microenvironment is essential to stem cell-based therapy for ischemic stroke,and spatiotemporal changes of the microenvironment in the pathological process provide vital clues for understanding the therapeutic mechanisms.However,relevant studies on microenvironmental changes were mainly confined in the acute phase of stroke,and long-term changes remain unclear.This study aimed to investigate the microenvironmental changes in the subacute and chronic phases of ischemic stroke after stem cell transplantation.Herein,induced pluripotent stem cells(iPSCs)and neural stem cells(NSCs)were transplanted into the ischemic brain established by middle cerebral artery occlusion surgery.Positron emission tomography imaging and neurological tests were applied to evaluate the metabolic and neurofunctional alterations of rats transplanted with stem cells.Quantitative proteomics was employed to investigate the protein expression profiles in iPSCs-transplanted brain in the subacute and chronic phases of stroke.Compared with NSCs-transplanted rats,significantly increased glucose metabolism and neurofunctional scores were observed in iPSCs-transplanted rats.Subsequent proteomic data of iPSCs-transplanted rats identified a total of 39 differentially expressed proteins in the subacute and chronic phases,which are involved in various ischemic stroke-related biological processes,including neuronal survival,axonal remodeling,antioxidative stress,and mitochondrial function restoration.Taken together,our study indicated that iPSCs have a positive therapeutic effect in ischemic stroke and emphasized the wide-ranging microenvironmental changes in the subacute and chronic phases.
基金the National Basic Research Program 973 program(No.2012CB966800)the Thousand Youth Talents Program and the Pioneer Programs of Chinese Academy of Sciences。
文摘Human embryonic stem cells(hESCs)are pluripotent cells that have the ability of unlimited self-renewal and can be differentiated into different cell lineages,includ-ing neural stem(NS)cells.Diverse regulatory signaling pathways of neural stem cells differentiation have been discovered,and this will be of great benefit to uncover the mechanisms of neuronal differentiation in vivo and in vitro.However,the limitations of hESCs resource along with the religious and ethical concerns impede the pro-gress of ESCs application.Therefore,the induced pluri-potent stem cells(iPSCs)via somatic cell reprogramming have opened up another new territory for regenerative medicine.iPSCs now can be derived from a number of lin-eages of cells,and are able to differentiate into certain cell types,including neurons.Patient-specifi c iPSCs are being used in human neurodegenerative disease modeling and drug screening.Furthermore,with the development of somatic direct reprogramming or lineage reprogramming technique,a more effective approach for regenerative medicine could become a complement for iPSCs.
基金We thank the National Natural Science Foundation of China(grants No.32171387 and 32071452)Shenzhen Bay Laboratory Open Program(grant No.SZBL2020090501003)the Pearl River Talents Program Local Innovative and Research Teams(grant No.2017BT01S131).
文摘In 2006,Takahashi and Yamanaka first created induced pluripotent stem cells from mouse fibroblasts via the retroviral introduction of genes encoding the transcription factors Oct3/4,Sox2,Klf44,and c-Myc.Since then,the future clinical application of somatic cell reprogramming technology has become an attractive research topic in the field of regenerative medicine.Of note,considerable interest has been placed in circumventing ethical issues linked to embryonic stem cell research.However,tumorigenicity,immunogenicity,and heterogeneity may hamper attempts to deploy this technology therapeutically.This review highlights the progress aimed at reducing induced pluripotent stem cells tumorigenicity risk and howto assess the safety of induced pluripotent stem cells cell therapy products.
基金the Natural Science Foundation of Fujian Province(2018J012345)。
文摘The purpose of this study was to primarily culture human periodontal ligament cells(hPDLCs)and to reprogram hPDLCs with exogenous genes via a lentivirus-mediated transfection system.Then induced pluripotent stem cells derived from h PDLCs(hPDLC-iPSCs)were identified.Alizarin red staining was used to observe the formation of mineralized nodules and real-time Polymerase Chain Reaction(PCR)was used to detect the expression of osteogenic genes.For the in vivo experiment,nude mouse skull defect models were established and cell sheets were made to repair the bone defect.The reprogrammed cells were positive for alkaline phosphatase(ALP)staining and embryonic stem cells(ESCs)-specific proteins,and could form teratomas.After osteogenic induction,alizarin red staining showed that the number of mineralized nodules in the h PDLC-i PSCs group was more and the osteogenic related factors ALP,osteocalcin(OCN),Col-I and Runx2 were also expressed higher in hPDLC-iPSCs.The hPDLC-iPSC cell sheets were all successfully made.Histological analysis showed that the h PDLC-i PSC cell sheet got new bone formation.These results demonstrated that hPDLC-iPSCs were successfully generated from human periodontal ligament fibroblasts and hPDLC-iPSC cell sheets provided new options for bone tissue engineering.
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.
文摘Progress of cell therapy for muscular dystrophies is slow. Although there are clinical trials of myoblast delivery, the result is not satisfactory. However, human stem cell especially induced pluripotent stem cells （iPSCs） could overcome the problem by successful differentiation. Generally speaking, there are two strategies for that goal one is by plasmid and the other is by differentiation factors in vitro. This review covers recent advances in the differentiation field of human embryonic stem cells （ESCs） and iPSCs, showing different differentiation methods as a potential therapy way.
文摘The stem cells of an organism only possess extraordinary capacity to change into different cell types during the early life and growth of an organism. When these stem cells divide into different new cells, these either remain as stem cells or develop to become other cells with specialized function. For this reason, stem cells offer direct relevance to human health, as theoretically, using stem cell technology, different organs are expected to be regenerated. To this, the Human Embryonic Stem Cells (HESCs) are natural pluripotent cell, but ethical issues covering many countries have put research work on a bit back-foot. However, the Induced Pluripotent Stem Cells (iPSCs) technology has completely revitalized the world to use this technology universally and it therefore seems that more research on this technology will surely be of enormous help in public health. In addition, application of the stem cell technology in personalized-medicine has been started recently. In this concern, the stem cell banking facilities have provided new avenues for preserving the cord blood of the new-borne child and treat them in future by using her/his own preserved stem cells. However, like all new technologies, the output from stem cell research requires to be evaluated more closely. Furthermore, with proper guidelines on ethical issues and extended research following these strategies, the stem cell technology is expected to not only be of huge benefit to human health, but also the benefit can be extended to the survival of endangered animals as well.
