A century has passed since the Nobel Prize winning discovery of insulin,which still remains the mainstay treatment for type 1 diabetes mellitus(T1DM)to this day.True to the words of its discoverer Sir Frederick Banti...A century has passed since the Nobel Prize winning discovery of insulin,which still remains the mainstay treatment for type 1 diabetes mellitus(T1DM)to this day.True to the words of its discoverer Sir Frederick Banting,“insulin is not a cure for diabetes,it is a treatment”,millions of people with T1DM are dependent on daily insulin medications for life.Clinical donor islet transplantation has proven that T1DM is curable,however due to profound shortages of donor islets,it is not a mainstream treatment option for T1DM.Human pluripotent stem cell derived insulin-secreting cells,pervasively known as stem cell-derivedβcells(SC-βcells),are a promising alternative source and have the potential to become a T1DM treatment through cell replacement therapy.Here we briefly review how isletβcells develop and mature in vivo and several types of reported SC-βcells produced using different ex vivo protocols in the last decade.Although some markers of maturation were expressed and glucose stimulated insulin secretion was shown,the SC-βcells have not been directly compared to their in vivo counterparts,generally have limited glucose response,and are not yet fully matured.Due to the presence of extra-pancreatic insulin-expressing cells,and ethical and technological issues,further clarification of the true nature of these SC-βcells is required.展开更多
Neurodevelopmental disorders are characterized by an abnormal development of the central nervous system, leading to a myriad of symptoms and diseases, including intellectual disability, attention deficits, impairments...Neurodevelopmental disorders are characterized by an abnormal development of the central nervous system, leading to a myriad of symptoms and diseases, including intellectual disability, attention deficits, impairments in learning and memory, speech disorders and repetitive behavior （Telias and Ben-Yosef, 2014）. Common major neurodevelopmental disorders include autism and autism spectrum disorders （ASDs）, fragile X syndrome （FXS）, Down syndrome （DS）, and Rett syndrome （RTT）. They can be collectively described as disorders in which the plasticity of the brain has been severely impaired. The concept of plasticity refers to the brain＇s ability to adapt to and process new information and react accordingly, and it can be classified into three categories： a） molecular plasticity, whenever specific receptors, ion channels, enzymes,展开更多
Numerous studies have shown that cell replacement therapy can replenish lost cells and rebuild neural circuitry in animal models of Parkinson’s disease.Transplantation of midbrain dopaminergic progenitor cells is a p...Numerous studies have shown that cell replacement therapy can replenish lost cells and rebuild neural circuitry in animal models of Parkinson’s disease.Transplantation of midbrain dopaminergic progenitor cells is a promising treatment for Parkinson’s disease.However,transplanted cells can be injured by mechanical damage during handling and by changes in the transplantation niche.Here,we developed a one-step biomanufacturing platform that uses small-aperture gelatin microcarriers to produce beads carrying midbrain dopaminergic progenitor cells.These beads allow midbrain dopaminergic progenitor cell differentiation and cryopreservation without digestion,effectively maintaining axonal integrity in vitro.Importantly,midbrain dopaminergic progenitor cell bead grafts showed increased survival and only mild immunoreactivity in vivo compared with suspended midbrain dopaminergic progenitor cell grafts.Overall,our findings show that these midbrain dopaminergic progenitor cell beads enhance the effectiveness of neuronal cell transplantation.展开更多
Cell replacement therapy utilizing mesenchymal stem cells as its main resource holds great promise for ultimate treatment of human neurological disorders.Parkinson＇s disease（PD）is a common,chronic neurodegenerative...Cell replacement therapy utilizing mesenchymal stem cells as its main resource holds great promise for ultimate treatment of human neurological disorders.Parkinson＇s disease（PD）is a common,chronic neurodegenerative disorder hallmarked by localized degeneration of a specific set of dopaminergic neurons within a midbrain sub-region.The specific cell type and confined location of degenerating neurons make cell replacement therapy ideal for PD treatment since it mainly requires replenishment of lost dopaminergic neurons with fresh and functional ones.Endogenous as well as exogenous cell sources have been identified as candidate targets for cell replacement therapy in PD.In this review,umbilical cord mesenchymal stem cells（UCMSCs）are discussed as they provide an inexpensive unlimited reservoir differentiable towards functional dopaminergic neurons that potentially lead to long-lasting behavioral recovery in PD patients.We also present mi RNAs-mediated neuronal differentiation of UCMSCs.The UCMSCs bear a number of outstanding characteristics including their non-tumorigenic,low-immunogenic properties that make them ideal for cell replacement therapy purposes.Nevertheless,more investigations as well as controlled clinical trials are required to thoroughly confirm the efficacy of UCMSCs for therapeutic medical-grade applications in PD.展开更多
BACKGROUND Despite the availability of current therapies,including oral antidiabetic drugs and insulin,for controlling the symptoms caused by high blood glucose,it is difficult to cure diabetes mellitus,especially typ...BACKGROUND Despite the availability of current therapies,including oral antidiabetic drugs and insulin,for controlling the symptoms caused by high blood glucose,it is difficult to cure diabetes mellitus,especially type 1 diabetes mellitus.AIM Cell therapies using mesenchymal stem cells(MSCs)may be a promising option.However,the therapeutic mechanisms by which MSCs exert their effects,such as whether they can differentiate into insulin-producing cells (IPCs) beforetransplantation, are uncertain.METHODSIn this study, we used three types of differentiation media over 10 d to generateIPCs from human Wharton’s jelly MSCs (hWJ-MSCs). We further transplantedthe undifferentiated hWJ-MSCs and differentiated IPCs derived from them intothe portal vein of rats with streptozotocin-induced diabetes, and recorded thephysiological and pathological changes.RESULTSUsing fluorescent staining and C-peptide enzyme-linked immunoassay, we wereable to successfully induce the differentiation of hWJ-MSCs into IPCs.Transplantation of both IPCs derived from hWJ-MSCs and undifferentiated hWJMSCshad the therapeutic effect of ameliorating blood glucose levels andimproving intraperitoneal glucose tolerance tests. The transplanted IPCs homedto the pancreas and functionally survived for at least 8 wk after transplantation,whereas the undifferentiated hWJ-MSCs were able to improve the insulitis andameliorate the serum inflammatory cytokine in streptozotocin-induced diabeticrats.CONCLUSIONDifferentiated IPCs can significantly improve blood glucose levels in diabetic ratsdue to the continuous secretion of insulin by transplanted cells that survive in theislets of diabetic rats. Transplantation of undifferentiated hWJ-MSCs cansignificantly improve insulitis and re-balance the inflammatory condition indiabetic rats with only a slight improvement in blood glucose levels.展开更多
Pancreatic insulin-secreting β-cells are essential regulators of glucose metabolism. New strategies are cur-rently being investigated to create insulin-producing β cells to replace deficient β cells, including the ...Pancreatic insulin-secreting β-cells are essential regulators of glucose metabolism. New strategies are cur-rently being investigated to create insulin-producing β cells to replace deficient β cells, including the differentiation of either stem or progenitor cells, and the newly uncovered transdifferentiation of mature non-β islet cell types. However, in order to correctly drive any cell to adopt a new β-cell fate, a better understanding of the in vivo mechanisms involved in the plasticity and biology of islet cells is urgently required. Here, we review the recent studies reporting the phenomenon of transdifferentiation of α cells into β cells by focusing on the major candidates and contexts revealed to be involved in adult β-cell regeneration through this process. The possible underlying mechanisms of transdifferentiation and the interactions between several key factors involved in the process are also addressed. We propose that it is of importance to further study the molecular and cellular mechanisms underlying α- to β-cell transdifferentiation, in order to make β-cell regeneration from α cells a relevant and realizable strategy for developing cell-replacement therapy.展开更多
Objective To determine whether continuous or cyclic hormone replacement therapy (estrogen and progestogen) is better.Methods One hundred and forty Sprague-Dawley rats were randomly divided into seven groups. The 1st...Objective To determine whether continuous or cyclic hormone replacement therapy (estrogen and progestogen) is better.Methods One hundred and forty Sprague-Dawley rats were randomly divided into seven groups. The 1st and 2nd groups were normal estrous and ovariectomy (OVX) controls. Treatment of the other groups imitated the clinical regimen (continuous and cyclic) with estradiol valerate (E2V) and medroxy progesterone (MPA) in different ratios of combination. The rats were sacrificed and sections of uterus were stained with HE and histochemical metheds to detect mitosis and proliferating cell nuclear antigen (PCNA), respectively. The mitotic index (MI) and PCNA index were calculated.Results The MI and PCNA index were similar in luminal and glandular cells. Both markers were low in the two control groups. When E2V was given for 1 to 6 days, both the MI and PCNA index increased with duration of treatment. When MPA was added, both markers were reduced to a very low level. In the continuous regimen, both markers decreased as the MPA dosage increased. The ratio of E2V∶MPA=1∶0.5 was enough to suppress markers to a low level similar to that of normal estrous rats. A further increase in the ratio to 1∶1.0 showed no further decrease in PCNA index. In the cyclic regimen, MPA was added for the last 5 days. The mitotic index reached a significantly low level near 0 in all ratios, but the PCNA index in each subgroup was still as high as the positive control, even though the dosage of MPA was increased several times to 1∶8.0. When MPA was added for the last 10 days, the PCNA index at a ratio of 1∶4.0 could be reduced to a low level.Conclusion The results of this study suggest that the continuous regimen was better than the cyclic regimen in postmenopausal hormone replacement therapy (HRT). Progestin should be given for at least 10 days in the cyclic regimen.展开更多
基金Supported by the Juvenile Diabetes Research Foundation,No.4-2006-1025Diabetes Australia Research TrustTelethon Perth Children’s Hospital Research Fund(TPCHRF)grant to Jiang FX.
文摘A century has passed since the Nobel Prize winning discovery of insulin,which still remains the mainstay treatment for type 1 diabetes mellitus(T1DM)to this day.True to the words of its discoverer Sir Frederick Banting,“insulin is not a cure for diabetes,it is a treatment”,millions of people with T1DM are dependent on daily insulin medications for life.Clinical donor islet transplantation has proven that T1DM is curable,however due to profound shortages of donor islets,it is not a mainstream treatment option for T1DM.Human pluripotent stem cell derived insulin-secreting cells,pervasively known as stem cell-derivedβcells(SC-βcells),are a promising alternative source and have the potential to become a T1DM treatment through cell replacement therapy.Here we briefly review how isletβcells develop and mature in vivo and several types of reported SC-βcells produced using different ex vivo protocols in the last decade.Although some markers of maturation were expressed and glucose stimulated insulin secretion was shown,the SC-βcells have not been directly compared to their in vivo counterparts,generally have limited glucose response,and are not yet fully matured.Due to the presence of extra-pancreatic insulin-expressing cells,and ethical and technological issues,further clarification of the true nature of these SC-βcells is required.
文摘Neurodevelopmental disorders are characterized by an abnormal development of the central nervous system, leading to a myriad of symptoms and diseases, including intellectual disability, attention deficits, impairments in learning and memory, speech disorders and repetitive behavior （Telias and Ben-Yosef, 2014）. Common major neurodevelopmental disorders include autism and autism spectrum disorders （ASDs）, fragile X syndrome （FXS）, Down syndrome （DS）, and Rett syndrome （RTT）. They can be collectively described as disorders in which the plasticity of the brain has been severely impaired. The concept of plasticity refers to the brain＇s ability to adapt to and process new information and react accordingly, and it can be classified into three categories： a） molecular plasticity, whenever specific receptors, ion channels, enzymes,
基金supported by the National Key Research and Development Program of China,Nos.2017YFE0122900(to BH),2019YFA0110800(to WL),2019YFA0903802(to YW),2021YFA1101604(to LW),2018YFA0108502(to LF),and 2020YFA0804003(to JW)the National Natural Science Foundation of China,Nos.31621004(to WL,BH)and 31970821(to YW)+1 种基金CAS Project for Young Scientists in Basic Research,No.YSBR-041(to YW)Joint Funds of the National Natural Science Foundation of China,No.U21A20396(to BH)。
文摘Numerous studies have shown that cell replacement therapy can replenish lost cells and rebuild neural circuitry in animal models of Parkinson’s disease.Transplantation of midbrain dopaminergic progenitor cells is a promising treatment for Parkinson’s disease.However,transplanted cells can be injured by mechanical damage during handling and by changes in the transplantation niche.Here,we developed a one-step biomanufacturing platform that uses small-aperture gelatin microcarriers to produce beads carrying midbrain dopaminergic progenitor cells.These beads allow midbrain dopaminergic progenitor cell differentiation and cryopreservation without digestion,effectively maintaining axonal integrity in vitro.Importantly,midbrain dopaminergic progenitor cell bead grafts showed increased survival and only mild immunoreactivity in vivo compared with suspended midbrain dopaminergic progenitor cell grafts.Overall,our findings show that these midbrain dopaminergic progenitor cell beads enhance the effectiveness of neuronal cell transplantation.
文摘Cell replacement therapy utilizing mesenchymal stem cells as its main resource holds great promise for ultimate treatment of human neurological disorders.Parkinson＇s disease（PD）is a common,chronic neurodegenerative disorder hallmarked by localized degeneration of a specific set of dopaminergic neurons within a midbrain sub-region.The specific cell type and confined location of degenerating neurons make cell replacement therapy ideal for PD treatment since it mainly requires replenishment of lost dopaminergic neurons with fresh and functional ones.Endogenous as well as exogenous cell sources have been identified as candidate targets for cell replacement therapy in PD.In this review,umbilical cord mesenchymal stem cells（UCMSCs）are discussed as they provide an inexpensive unlimited reservoir differentiable towards functional dopaminergic neurons that potentially lead to long-lasting behavioral recovery in PD patients.We also present mi RNAs-mediated neuronal differentiation of UCMSCs.The UCMSCs bear a number of outstanding characteristics including their non-tumorigenic,low-immunogenic properties that make them ideal for cell replacement therapy purposes.Nevertheless,more investigations as well as controlled clinical trials are required to thoroughly confirm the efficacy of UCMSCs for therapeutic medical-grade applications in PD.
基金Taipei Veterans General Hospital,No.V106B-024Yen Tjing Ling Medical Foundation,No.CI-106-20+1 种基金Cheng Hsin General Hospital,No.CY10716Taiwan Ministry of Science and Technology,No.MOST 105-2314-B-010-010-MY3 and No.MOST 106-2314-B-010-009
文摘BACKGROUND Despite the availability of current therapies,including oral antidiabetic drugs and insulin,for controlling the symptoms caused by high blood glucose,it is difficult to cure diabetes mellitus,especially type 1 diabetes mellitus.AIM Cell therapies using mesenchymal stem cells(MSCs)may be a promising option.However,the therapeutic mechanisms by which MSCs exert their effects,such as whether they can differentiate into insulin-producing cells (IPCs) beforetransplantation, are uncertain.METHODSIn this study, we used three types of differentiation media over 10 d to generateIPCs from human Wharton’s jelly MSCs (hWJ-MSCs). We further transplantedthe undifferentiated hWJ-MSCs and differentiated IPCs derived from them intothe portal vein of rats with streptozotocin-induced diabetes, and recorded thephysiological and pathological changes.RESULTSUsing fluorescent staining and C-peptide enzyme-linked immunoassay, we wereable to successfully induce the differentiation of hWJ-MSCs into IPCs.Transplantation of both IPCs derived from hWJ-MSCs and undifferentiated hWJMSCshad the therapeutic effect of ameliorating blood glucose levels andimproving intraperitoneal glucose tolerance tests. The transplanted IPCs homedto the pancreas and functionally survived for at least 8 wk after transplantation,whereas the undifferentiated hWJ-MSCs were able to improve the insulitis andameliorate the serum inflammatory cytokine in streptozotocin-induced diabeticrats.CONCLUSIONDifferentiated IPCs can significantly improve blood glucose levels in diabetic ratsdue to the continuous secretion of insulin by transplanted cells that survive in theislets of diabetic rats. Transplantation of undifferentiated hWJ-MSCs cansignificantly improve insulitis and re-balance the inflammatory condition indiabetic rats with only a slight improvement in blood glucose levels.
基金Supported by The Agence National de Recherche(ANR 2010 BLAN 1240 01)the Ligue contre le Cancer du Rh ne and de la Loire+3 种基金the CMIRA program of Region Rh?ne-Alpes,No.12004959-01the Fondation ARC pour la Recherche sur le Cancer,France,No.SFI20101201530National Nature Science Foundation of China,No.NSFC81170719,No.81370960Shanghai New Excellent Youth Program,No.XYQ2011009
文摘Pancreatic insulin-secreting β-cells are essential regulators of glucose metabolism. New strategies are cur-rently being investigated to create insulin-producing β cells to replace deficient β cells, including the differentiation of either stem or progenitor cells, and the newly uncovered transdifferentiation of mature non-β islet cell types. However, in order to correctly drive any cell to adopt a new β-cell fate, a better understanding of the in vivo mechanisms involved in the plasticity and biology of islet cells is urgently required. Here, we review the recent studies reporting the phenomenon of transdifferentiation of α cells into β cells by focusing on the major candidates and contexts revealed to be involved in adult β-cell regeneration through this process. The possible underlying mechanisms of transdifferentiation and the interactions between several key factors involved in the process are also addressed. We propose that it is of importance to further study the molecular and cellular mechanisms underlying α- to β-cell transdifferentiation, in order to make β-cell regeneration from α cells a relevant and realizable strategy for developing cell-replacement therapy.
文摘Objective To determine whether continuous or cyclic hormone replacement therapy (estrogen and progestogen) is better.Methods One hundred and forty Sprague-Dawley rats were randomly divided into seven groups. The 1st and 2nd groups were normal estrous and ovariectomy (OVX) controls. Treatment of the other groups imitated the clinical regimen (continuous and cyclic) with estradiol valerate (E2V) and medroxy progesterone (MPA) in different ratios of combination. The rats were sacrificed and sections of uterus were stained with HE and histochemical metheds to detect mitosis and proliferating cell nuclear antigen (PCNA), respectively. The mitotic index (MI) and PCNA index were calculated.Results The MI and PCNA index were similar in luminal and glandular cells. Both markers were low in the two control groups. When E2V was given for 1 to 6 days, both the MI and PCNA index increased with duration of treatment. When MPA was added, both markers were reduced to a very low level. In the continuous regimen, both markers decreased as the MPA dosage increased. The ratio of E2V∶MPA=1∶0.5 was enough to suppress markers to a low level similar to that of normal estrous rats. A further increase in the ratio to 1∶1.0 showed no further decrease in PCNA index. In the cyclic regimen, MPA was added for the last 5 days. The mitotic index reached a significantly low level near 0 in all ratios, but the PCNA index in each subgroup was still as high as the positive control, even though the dosage of MPA was increased several times to 1∶8.0. When MPA was added for the last 10 days, the PCNA index at a ratio of 1∶4.0 could be reduced to a low level.Conclusion The results of this study suggest that the continuous regimen was better than the cyclic regimen in postmenopausal hormone replacement therapy (HRT). Progestin should be given for at least 10 days in the cyclic regimen.
