“Stem Cells is what stem cells does” ... “Stem Cells is what stem cells does” not Forrest Gump In the present day Stem Cells are increasingly becoming popularized as the potential “ultimate” cure for the most challenging maladies… the “Daddy of medical intervention”. Forefront SC research on human induced pluripotent stem cells (iPSCs) and other sub-disciplines, is quickly revolutionizing healthcare towards “Regenerative Medicine”, as beautifully exemplified by the use of iPSCs in treating and possibly curing osteoarthritis, discussed at the end of this publication. This review documents and reflects on the most topical discoveries in SC research, and the challenges researchers in this field nowadays face. Major Findings: 1) In 2006 Yamanaka et al. generated the first iPSCs from mouse fibroblasts, using retroviral transmission of c-Myc, Oct3/4, Klf4 and SOX2 transcription factors. Later, they successfully generated iPSCs from human fibroblasts (2007). 2) Contemporary cultivation methods carry high risks of iPSC genome disruption, possibly leading to tumorigenesis, teratoma formation and reducing iPSC induction efficacy. 3) Many studies on preserving genome integrity and decreasing malignancy in iPSCs, suggest using valiproic acid and protecting tumour suppressor genes. 4) In many malignant tumours only a small minority of cells, called Cancer Stem Cells, metastasise and hyper-proliferate. 5) Not all mature cell sources yield the same [undifferentiated iPSCs: lineage-committed] ratio as others. Feb 2014: Obokata et al. claimed to have generated iPSCs by exposing mature cells to a 25 min, pH 5.7 bath. These iPSCs were termed “Stimulus-triggered Acquisition Pluripotency Cells” (STAP). However by July 2014 this study had been revoked, as the results could not be replicated. Conclusion: Stem cells have enormous potential to offer, especially iPSCs. Although currently not a viable treatment option on their own, for many daunting diseases they will definitely be at the core of multi-disciplined therapies within the near-future, including multi-factorial diseases like osteoarthritis.展开更多
Inflammatory bowel diseases are inflammatory, chronic and progressive diseases of the intestinal tract for which no curative treatment is available. Research in other fields with stem cells of different sources and wi...Inflammatory bowel diseases are inflammatory, chronic and progressive diseases of the intestinal tract for which no curative treatment is available. Research in other fields with stem cells of different sources and with immunoregulatory cells(regulatory T-lymphocytes and dendritic T-cells) opens up new expectations for their use in these diseases. The goal for stem cell-based therapy is to provide a permanent cure. To achieve this, it will be necessary to obtain a cellular product, original or genetically modified, that has a high migration capacity and homes into the intestine, has high survival after transplantation, regulates the immune reaction while not being visible to the patient's immune system, and repairs the injured tissue.展开更多
Pluripotent stem cells are unspecialized cells withunlimited self-renewal, and they can be triggered to differentiate into desired specialized cell types. These features provide the basis for an unlimited cell source ...Pluripotent stem cells are unspecialized cells withunlimited self-renewal, and they can be triggered to differentiate into desired specialized cell types. These features provide the basis for an unlimited cell source for innovative cell therapies. Pluripotent cells also allow to study developmental pathways, and to employ them or their differentiated cell derivatives in pharmaceutical testing and biotechnological applications. Via blastocyst complementation, pluripotent cells are a favoured tool for the generation of genetically modified mice. The recently established technology to generate an induced pluripotency status by ectopic co-expression of the transcription factors Oct4, Sox2, Klf4 and c-Myc allows to extending these applications to farm animal species, for which the derivation of genuine embryonic stem cells was not successful so far. Most induced pluripotent stem(i PS) cells are generated by retroviral or lentiviral transduction of reprogramming factors. Multiple viral integrations into the genome may cause insertional mutagenesis and may increase the risk of tumour formation. Non-integration methods have been reported to overcome the safety concerns associated with retro and lentiviral-derived i PS cells, such as transient expression of the reprogramming factors using episomal plasmids, and direct delivery of reprogramming m RNAs or proteins. In this review, we focus on the mechanisms of cellular reprogramming and current methods used to induce pluripotency. We also highlight problems associated with the generation of i PS cells. An increased understanding of the fundamental mechanisms underlying pluripotency and refining the methodology of i PS cell generation will have a profound impact on future development and application in regenerative medicine and reproductive biotechnology of farm animals.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
Pathogenic mutations involving DNA repeat expansions are responsible for over 20 different neuronal and neuromuscular diseases. All result from expanded tracts of repetitive DNA sequences(mostly microsatellites) that ...Pathogenic mutations involving DNA repeat expansions are responsible for over 20 different neuronal and neuromuscular diseases. All result from expanded tracts of repetitive DNA sequences(mostly microsatellites) that become unstable beyond a critical length whentransmitted across generations. Nearly all are inherited as autosomal dominant conditions and are typically associated with anticipation. Pathologic unstable repeat expansions can be classified according to their length, repeat sequence, gene location and underlying pathologic mechanisms. This review summarizes the current contribution of mutant pluripotent stem cells(diseased human embryonic stem cells and patient-derived induced pluripotent stem cells) to the research of unstable repeat pathologies by focusing on particularly large unstable noncoding expansions. Among this class of disorders are Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome, myotonic dystrophy type 1 and myotonic dystrophy type 2, Friedreich ataxia and C9 related amyotrophic lateral sclerosis and/or frontotemporal dementia, Facioscapulohumeral Muscular Dystrophy and potentially more. Common features that are typical to this subclass of conditions are RNA toxic gain-of-function, epigenetic loss-of-function, toxic repeat-associated non-ATG translation and somatic instability. For each mechanism we summarize the currently available stem cell based models, highlight how they contributed to better understanding of the related mechanism, and discuss how they may be utilized in future investigations.展开更多
More than two decades of in vitro experimentation supported by the data from experimental animal studies in both small as well as large experimental animal models have culminated into multiple clinical studies worldwi...More than two decades of in vitro experimentation supported by the data from experimental animal studies in both small as well as large experimental animal models have culminated into multiple clinical studies worldwide to assess their regenerative potential. Although the data generated from these studies have only met with cautious response from the researchers, efforts are still underway with the hope to refine the different aspects of cell-based therapy approach to develop it into an effective routine therapeutic intervention. Besides others, search for a cell type with optimal characteristics remains an area of intense research. Pluripotent stem cells in general, and induced pluripotent stem cells in particular have gained special attention of researchers due to their ability to adopt a morphofuntionally competent phenotype. They are being considered as surrogate embryonic stem cells albeit without moral and ethical issues of availability and having better immunological acceptability. We provide a head-to-head comparison of ESCs and iPSCs and an overview of stem cell therapy approach converging on the observed advantages of pluripotent stem cells during pre-clinical and clinical studies.展开更多
OBJECTIVE To establish an in vitro cel model based on patient-specific human microglia to study the pathological mechanism of Alzheimer disease(AD) and to screen candidate drugs.METHODS First,the induced pluripotent s...OBJECTIVE To establish an in vitro cel model based on patient-specific human microglia to study the pathological mechanism of Alzheimer disease(AD) and to screen candidate drugs.METHODS First,the induced pluripotent stem cells(iPSCs) of AD patients and cognitive normal controls(CNC) were induced to hematopoietic progenitor cells(HPCs),and then HPCs were further induced with IL-34,M-CSF,GM-CSF and TGF-β1 for 20 d to obtain microglialike cells(MGLCs).HPCs were isolated by flow cytometry and MGLCs were identified by immunofluorescence.Cell phagocytosis was determined by phagocytosis neutral red experiusing Luminex assay kits,and the cell growth curve during the experiment was recorded by IncuCyte ZOOM.The phagocytic ability and secretion of cytokines of MGLCs were observed under the stimulation of LPS.RESULTS MGLCs from AD patients(AD-MGLCs) and CNC expressed microglia markers IBA1,TMEM119,P2 RY12,TREM2 and CD11 B.The results of phagocytosis neutral red experiment showed that under normal conditions,AD-MGLCs had stronger phagocytic ability(P<0.01).Stimulation by LPS resulted in increased phagocytosis of cel s,and the increase in phagocytosis of CNC-MGLCs was higher than AD-MGLCs(P<0.01).Experiments showed that high concentrations of LPS(>2 mg·L^(-1)) resulted in CNC-microglia death(P<0.01),whereas ADMGLCs did not show significant death.The cytokine assay showed that under normal conditions,the concentrations of IFN-γ and IL-2 secreted by AD patients were slightly higher than those of CNC.After LPS stimulation,the secretion of TNF-α,IL-6 and IL-10 was significantly increased.The increased secretion of AD-MGLCs was greater than that CNC-MGLCs(P<0.01).CONCLUSION AD-iPSCs derived MGLCs exhibit significant inflammatory characteristics and are more active than CNC,which may be associated with chronic inflammatory responses caused by microglia in AD,thus may provide valuable new tools to screen candidate drugs for the disease and to discover the mechanisms underlying AD pathogenesis.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
The identification of a single, early marker for full developmental potential of induced pluripotent stem (iPS) cells has proven elusive. Recently, however, activation of the imprinted gene cluster, Dlk1-Dio3 has emer...The identification of a single, early marker for full developmental potential of induced pluripotent stem (iPS) cells has proven elusive. Recently, however, activation of the imprinted gene cluster, Dlk1-Dio3 has emerged as a viable candidate in the mouse. To explore the relationship between Dlk1-Dio3 expression and developmental potential more fully, we used murine ear mesenchymal stem cells (mEMSC) for iPS cell induction. Mouse EMSC are easily obtained and share functional characteristics with embryonic stem (ES) cells and therefore, may be a reliable non-embryonic source for iPS cell production. We report that mEMSC express high levels of Gtl2, a maternally expressed gene within the Dlk1-Dio3 imprinted cluster. Moreover, mEMSC produce Gtl2 expressing (Gtl2on) iPSC clones that share functional characteristics with ES cell clones. The production of Gtl2on iPS cell clones from mEMSC provides a new model with which to investigate the regulation of Dlk1-Dio3 cluster activity during direct cell reprogramming.展开更多
溴结构域和超末端结构域(bromodomain and extra-terminal,BET)蛋白家族作为表观"阅读器",在哺乳动物发育过程中起着至关重要的作用。其家族内的各成员通过识别各种表观修饰并募集相应的功能复合物,对相关基因进行精密调控,...溴结构域和超末端结构域(bromodomain and extra-terminal,BET)蛋白家族作为表观"阅读器",在哺乳动物发育过程中起着至关重要的作用。其家族内的各成员通过识别各种表观修饰并募集相应的功能复合物,对相关基因进行精密调控,促使早期胚胎向特定方向分化和发育。另外,随着诱导性多潜能干细胞(induced pluripotent stem cell,iPSC)重编程技术发展,越来越多的研究发现BET蛋白家族在体细胞重编程中可能也占据着核心地位。本文总结了BET蛋白家族在哺乳动物发育和iPSC重编程中的作用,并对BET家族调控重编程的新机制进行了展望。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
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
文摘 “Stem Cells is what stem cells does” not Forrest Gump In the present day Stem Cells are increasingly becoming popularized as the potential “ultimate” cure for the most challenging maladies… the “Daddy of medical intervention”. Forefront SC research on human induced pluripotent stem cells (iPSCs) and other sub-disciplines, is quickly revolutionizing healthcare towards “Regenerative Medicine”, as beautifully exemplified by the use of iPSCs in treating and possibly curing osteoarthritis, discussed at the end of this publication. This review documents and reflects on the most topical discoveries in SC research, and the challenges researchers in this field nowadays face. Major Findings: 1) In 2006 Yamanaka et al. generated the first iPSCs from mouse fibroblasts, using retroviral transmission of c-Myc, Oct3/4, Klf4 and SOX2 transcription factors. Later, they successfully generated iPSCs from human fibroblasts (2007). 2) Contemporary cultivation methods carry high risks of iPSC genome disruption, possibly leading to tumorigenesis, teratoma formation and reducing iPSC induction efficacy. 3) Many studies on preserving genome integrity and decreasing malignancy in iPSCs, suggest using valiproic acid and protecting tumour suppressor genes. 4) In many malignant tumours only a small minority of cells, called Cancer Stem Cells, metastasise and hyper-proliferate. 5) Not all mature cell sources yield the same [undifferentiated iPSCs: lineage-committed] ratio as others. Feb 2014: Obokata et al. claimed to have generated iPSCs by exposing mature cells to a 25 min, pH 5.7 bath. These iPSCs were termed “Stimulus-triggered Acquisition Pluripotency Cells” (STAP). However by July 2014 this study had been revoked, as the results could not be replicated. Conclusion: Stem cells have enormous potential to offer, especially iPSCs. Although currently not a viable treatment option on their own, for many daunting diseases they will definitely be at the core of multi-disciplined therapies within the near-future, including multi-factorial diseases like osteoarthritis.
文摘Inflammatory bowel diseases are inflammatory, chronic and progressive diseases of the intestinal tract for which no curative treatment is available. Research in other fields with stem cells of different sources and with immunoregulatory cells(regulatory T-lymphocytes and dendritic T-cells) opens up new expectations for their use in these diseases. The goal for stem cell-based therapy is to provide a permanent cure. To achieve this, it will be necessary to obtain a cellular product, original or genetically modified, that has a high migration capacity and homes into the intestine, has high survival after transplantation, regulates the immune reaction while not being visible to the patient's immune system, and repairs the injured tissue.
基金Supported by CREST fellowship from Department of Biotechnology,Ministry of Science and Technology,Government of India(DK)International fellowship for Ph D from ICAR(TRT),Government of IndiaInternational training in generation of i PS cells from NAIP,ICAR,Government of India(TA)
文摘Pluripotent stem cells are unspecialized cells withunlimited self-renewal, and they can be triggered to differentiate into desired specialized cell types. These features provide the basis for an unlimited cell source for innovative cell therapies. Pluripotent cells also allow to study developmental pathways, and to employ them or their differentiated cell derivatives in pharmaceutical testing and biotechnological applications. Via blastocyst complementation, pluripotent cells are a favoured tool for the generation of genetically modified mice. The recently established technology to generate an induced pluripotency status by ectopic co-expression of the transcription factors Oct4, Sox2, Klf4 and c-Myc allows to extending these applications to farm animal species, for which the derivation of genuine embryonic stem cells was not successful so far. Most induced pluripotent stem(i PS) cells are generated by retroviral or lentiviral transduction of reprogramming factors. Multiple viral integrations into the genome may cause insertional mutagenesis and may increase the risk of tumour formation. Non-integration methods have been reported to overcome the safety concerns associated with retro and lentiviral-derived i PS cells, such as transient expression of the reprogramming factors using episomal plasmids, and direct delivery of reprogramming m RNAs or proteins. In this review, we focus on the mechanisms of cellular reprogramming and current methods used to induce pluripotency. We also highlight problems associated with the generation of i PS cells. An increased understanding of the fundamental mechanisms underlying pluripotency and refining the methodology of i PS cell generation will have a profound impact on future development and application in regenerative medicine and reproductive biotechnology of farm animals.
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.
文摘Pathogenic mutations involving DNA repeat expansions are responsible for over 20 different neuronal and neuromuscular diseases. All result from expanded tracts of repetitive DNA sequences(mostly microsatellites) that become unstable beyond a critical length whentransmitted across generations. Nearly all are inherited as autosomal dominant conditions and are typically associated with anticipation. Pathologic unstable repeat expansions can be classified according to their length, repeat sequence, gene location and underlying pathologic mechanisms. This review summarizes the current contribution of mutant pluripotent stem cells(diseased human embryonic stem cells and patient-derived induced pluripotent stem cells) to the research of unstable repeat pathologies by focusing on particularly large unstable noncoding expansions. Among this class of disorders are Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome, myotonic dystrophy type 1 and myotonic dystrophy type 2, Friedreich ataxia and C9 related amyotrophic lateral sclerosis and/or frontotemporal dementia, Facioscapulohumeral Muscular Dystrophy and potentially more. Common features that are typical to this subclass of conditions are RNA toxic gain-of-function, epigenetic loss-of-function, toxic repeat-associated non-ATG translation and somatic instability. For each mechanism we summarize the currently available stem cell based models, highlight how they contributed to better understanding of the related mechanism, and discuss how they may be utilized in future investigations.
文摘More than two decades of in vitro experimentation supported by the data from experimental animal studies in both small as well as large experimental animal models have culminated into multiple clinical studies worldwide to assess their regenerative potential. Although the data generated from these studies have only met with cautious response from the researchers, efforts are still underway with the hope to refine the different aspects of cell-based therapy approach to develop it into an effective routine therapeutic intervention. Besides others, search for a cell type with optimal characteristics remains an area of intense research. Pluripotent stem cells in general, and induced pluripotent stem cells in particular have gained special attention of researchers due to their ability to adopt a morphofuntionally competent phenotype. They are being considered as surrogate embryonic stem cells albeit without moral and ethical issues of availability and having better immunological acceptability. We provide a head-to-head comparison of ESCs and iPSCs and an overview of stem cell therapy approach converging on the observed advantages of pluripotent stem cells during pre-clinical and clinical studies.
基金National Key Research and Development Program(2016YFC1306301).
文摘OBJECTIVE To establish an in vitro cel model based on patient-specific human microglia to study the pathological mechanism of Alzheimer disease(AD) and to screen candidate drugs.METHODS First,the induced pluripotent stem cells(iPSCs) of AD patients and cognitive normal controls(CNC) were induced to hematopoietic progenitor cells(HPCs),and then HPCs were further induced with IL-34,M-CSF,GM-CSF and TGF-β1 for 20 d to obtain microglialike cells(MGLCs).HPCs were isolated by flow cytometry and MGLCs were identified by immunofluorescence.Cell phagocytosis was determined by phagocytosis neutral red experiusing Luminex assay kits,and the cell growth curve during the experiment was recorded by IncuCyte ZOOM.The phagocytic ability and secretion of cytokines of MGLCs were observed under the stimulation of LPS.RESULTS MGLCs from AD patients(AD-MGLCs) and CNC expressed microglia markers IBA1,TMEM119,P2 RY12,TREM2 and CD11 B.The results of phagocytosis neutral red experiment showed that under normal conditions,AD-MGLCs had stronger phagocytic ability(P<0.01).Stimulation by LPS resulted in increased phagocytosis of cel s,and the increase in phagocytosis of CNC-MGLCs was higher than AD-MGLCs(P<0.01).Experiments showed that high concentrations of LPS(>2 mg·L^(-1)) resulted in CNC-microglia death(P<0.01),whereas ADMGLCs did not show significant death.The cytokine assay showed that under normal conditions,the concentrations of IFN-γ and IL-2 secreted by AD patients were slightly higher than those of CNC.After LPS stimulation,the secretion of TNF-α,IL-6 and IL-10 was significantly increased.The increased secretion of AD-MGLCs was greater than that CNC-MGLCs(P<0.01).CONCLUSION AD-iPSCs derived MGLCs exhibit significant inflammatory characteristics and are more active than CNC,which may be associated with chronic inflammatory responses caused by microglia in AD,thus may provide valuable new tools to screen candidate drugs for the disease and to discover the mechanisms underlying AD pathogenesis.
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.
文摘The identification of a single, early marker for full developmental potential of induced pluripotent stem (iPS) cells has proven elusive. Recently, however, activation of the imprinted gene cluster, Dlk1-Dio3 has emerged as a viable candidate in the mouse. To explore the relationship between Dlk1-Dio3 expression and developmental potential more fully, we used murine ear mesenchymal stem cells (mEMSC) for iPS cell induction. Mouse EMSC are easily obtained and share functional characteristics with embryonic stem (ES) cells and therefore, may be a reliable non-embryonic source for iPS cell production. We report that mEMSC express high levels of Gtl2, a maternally expressed gene within the Dlk1-Dio3 imprinted cluster. Moreover, mEMSC produce Gtl2 expressing (Gtl2on) iPSC clones that share functional characteristics with ES cell clones. The production of Gtl2on iPS cell clones from mEMSC provides a new model with which to investigate the regulation of Dlk1-Dio3 cluster activity during direct cell reprogramming.
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.
