The heart has been considered a post-mitotic organ without regenerative capacity for most of the last century.We review the evidence that led to this hypothesis in the early 1900s and how it was progressively modified...The heart has been considered a post-mitotic organ without regenerative capacity for most of the last century.We review the evidence that led to this hypothesis in the early 1900s and how it was progressively modified,culminating with the report that we renew 50% of our cardiomyocytes during our lifetime.The future of cardiac regenerative therapies is discussed,presenting the difficulties to overcome before repair of the diseased heart can come into clinical practice.展开更多
Cardiovascular diseases represent the world’s leading cause of death. In thisheterogeneous group of diseases, ischemic cardiomyopathies are the mostdevastating and prevalent, estimated to cause 17.9 million deaths pe...Cardiovascular diseases represent the world’s leading cause of death. In thisheterogeneous group of diseases, ischemic cardiomyopathies are the mostdevastating and prevalent, estimated to cause 17.9 million deaths per year.Despite all biomedical efforts, there are no effective treatments that can replacethe myocytes lost during an ischemic event or progression of the disease to heartfailure. In this context, cell therapy is an emerging therapeutic alternative to treatcardiovascular diseases by cell administration, aimed at cardiac regeneration andrepair. In this review, we will cover more than 30 years of cell therapy in cardiology,presenting the main milestones and drawbacks in the field and signalingfuture challenges and perspectives. The outcomes of cardiac cell therapies arediscussed in three distinct aspects: The search for remuscularization byreplacement of lost cells by exogenous adult cells, the endogenous stem cell era,which pursued the isolation of a progenitor with the ability to induce heart repair,and the utilization of pluripotent stem cells as a rich and reliable source ofcardiomyocytes. Acellular therapies using cell derivatives, such as microvesiclesand exosomes, are presented as a promising cell-free therapeutic alternative.展开更多
AIM:To investigate the contribution of bone marrow(BM) cells to hepatic fibrosis.METHODS:To establish a model of chimerism,C57Bl/6 female mice were subjected to full-body irradiation(7 Gy) resulting in BM myeloablatio...AIM:To investigate the contribution of bone marrow(BM) cells to hepatic fibrosis.METHODS:To establish a model of chimerism,C57Bl/6 female mice were subjected to full-body irradiation(7 Gy) resulting in BM myeloablation.BM mononuclear cells obtained from male transgenic mice expressing enhanced green fluorescent protein(GFP) were used for reconstitution.Engraftment was confirmed by flow cytometry.To induce liver injury,chimeric animals received carbon tetrachloride(CCl4) 0.5 mL/kg intraperitoneally twice a week for 30 d(CCl4 30 d) and age-matched controls received saline(Saline 30 d).At the end of this period,animals were sacrificed for post mortem analysis.Liver samples were stained with hematoxylin and eosin to observe liver architectural changes and with Sirius red for collagen quantification by morphometric analysis.α-smooth muscle actin(α-SMA) was analyzed by confocal microscopy to identify GFP+ cells with myofibroblast(MF) characteristics.Liver tissue,BM and peripheral blood were collected and prepared for flow cytometric analysis using specific markers for detection of hepatic stellate cells(HSCs) and precursors from the BM.RESULTS:Injury to the liver induced changes in the hepatic parenchymal architecture,as reflected by the presence of inflammatory infiltrate and an increase in collagen deposition(Saline 30 d = 11.10% ± 1.12% vs CCl4 30 d = 12.60% ± 0.73%,P = 0.0329).Confocal microscopy revealed increased reactivity against α-SMA in CCl4 30 d compared to Saline 30 d,but there was no co-localization with GFP+ cells,suggesting that cells from BM do not differentiate to MFs.Liver flow cytometric analysis showed a significant increase of CD45+/GFP+ cells in liver tissue(Saline 30 d = 3.2% ± 2.2% vs CCl4 30 d = 5.8% ± 1.3%,P = 0.0458),suggesting that this increase was due to inflammatory cell infiltration(neutrophils and monocytes).There was also a significant increase of common myeloid progenitor cells(CD117+/CD45+) in the livers of CCl4-treated animals(Saline 30 d = 2.16% ± 1.80% vs CCl4 30 d = 5.60% ± 1.30%,P = 0.0142).In addition the GFP-/CD38+/CD45-subpopulation was significantly increased in the CCl4 30 d group compared to the Saline 30 d group(17.5% ± 3.9% vs 9.3% ± 2.4%,P = 0.004),indicating that the increase in the activated HSC subpopulation was not of BM origin.CONCLUSION:BM progenitor cells do not contribute to fibrosis,but there is a high recruitment of inflammatory cells that stimulates HSCs and MFs of liver origin.? 2012 Baishideng.All rights reserved.展开更多
After the demonstration that somatic cells could be reprogrammed to a pluripotent state,exciting new prospects were opened for the cardiac regeneration field.It did not take long for the development of strategies to c...After the demonstration that somatic cells could be reprogrammed to a pluripotent state,exciting new prospects were opened for the cardiac regeneration field.It did not take long for the development of strategies to convert somatic cells directly into cardiomyocytes.Despite the intrinsic difficulties of cell reprogramming,such as low efficiency,the therapeutic possibilities created by the ability to turn scar into muscle are enormous.Here,we discuss some of the major advances and strategies used in direct cardiac reprogramming and examine discrepancies and concerns that still need to be resolved in the field.展开更多
文摘The heart has been considered a post-mitotic organ without regenerative capacity for most of the last century.We review the evidence that led to this hypothesis in the early 1900s and how it was progressively modified,culminating with the report that we renew 50% of our cardiomyocytes during our lifetime.The future of cardiac regenerative therapies is discussed,presenting the difficulties to overcome before repair of the diseased heart can come into clinical practice.
基金Rio de Janeiro State Research Foundation,No.252042,No.250671 and No.241703.
文摘Cardiovascular diseases represent the world’s leading cause of death. In thisheterogeneous group of diseases, ischemic cardiomyopathies are the mostdevastating and prevalent, estimated to cause 17.9 million deaths per year.Despite all biomedical efforts, there are no effective treatments that can replacethe myocytes lost during an ischemic event or progression of the disease to heartfailure. In this context, cell therapy is an emerging therapeutic alternative to treatcardiovascular diseases by cell administration, aimed at cardiac regeneration andrepair. In this review, we will cover more than 30 years of cell therapy in cardiology,presenting the main milestones and drawbacks in the field and signalingfuture challenges and perspectives. The outcomes of cardiac cell therapies arediscussed in three distinct aspects: The search for remuscularization byreplacement of lost cells by exogenous adult cells, the endogenous stem cell era,which pursued the isolation of a progenitor with the ability to induce heart repair,and the utilization of pluripotent stem cells as a rich and reliable source ofcardiomyocytes. Acellular therapies using cell derivatives, such as microvesiclesand exosomes, are presented as a promising cell-free therapeutic alternative.
基金Supported by Brazilian Council for Scientific and Technological DevelopmentCoordination for the Improvement of Higher Education PersonnelRio de Janeiro State Research Supporting Foundation and Ministry of Health
文摘AIM:To investigate the contribution of bone marrow(BM) cells to hepatic fibrosis.METHODS:To establish a model of chimerism,C57Bl/6 female mice were subjected to full-body irradiation(7 Gy) resulting in BM myeloablation.BM mononuclear cells obtained from male transgenic mice expressing enhanced green fluorescent protein(GFP) were used for reconstitution.Engraftment was confirmed by flow cytometry.To induce liver injury,chimeric animals received carbon tetrachloride(CCl4) 0.5 mL/kg intraperitoneally twice a week for 30 d(CCl4 30 d) and age-matched controls received saline(Saline 30 d).At the end of this period,animals were sacrificed for post mortem analysis.Liver samples were stained with hematoxylin and eosin to observe liver architectural changes and with Sirius red for collagen quantification by morphometric analysis.α-smooth muscle actin(α-SMA) was analyzed by confocal microscopy to identify GFP+ cells with myofibroblast(MF) characteristics.Liver tissue,BM and peripheral blood were collected and prepared for flow cytometric analysis using specific markers for detection of hepatic stellate cells(HSCs) and precursors from the BM.RESULTS:Injury to the liver induced changes in the hepatic parenchymal architecture,as reflected by the presence of inflammatory infiltrate and an increase in collagen deposition(Saline 30 d = 11.10% ± 1.12% vs CCl4 30 d = 12.60% ± 0.73%,P = 0.0329).Confocal microscopy revealed increased reactivity against α-SMA in CCl4 30 d compared to Saline 30 d,but there was no co-localization with GFP+ cells,suggesting that cells from BM do not differentiate to MFs.Liver flow cytometric analysis showed a significant increase of CD45+/GFP+ cells in liver tissue(Saline 30 d = 3.2% ± 2.2% vs CCl4 30 d = 5.8% ± 1.3%,P = 0.0458),suggesting that this increase was due to inflammatory cell infiltration(neutrophils and monocytes).There was also a significant increase of common myeloid progenitor cells(CD117+/CD45+) in the livers of CCl4-treated animals(Saline 30 d = 2.16% ± 1.80% vs CCl4 30 d = 5.60% ± 1.30%,P = 0.0142).In addition the GFP-/CD38+/CD45-subpopulation was significantly increased in the CCl4 30 d group compared to the Saline 30 d group(17.5% ± 3.9% vs 9.3% ± 2.4%,P = 0.004),indicating that the increase in the activated HSC subpopulation was not of BM origin.CONCLUSION:BM progenitor cells do not contribute to fibrosis,but there is a high recruitment of inflammatory cells that stimulates HSCs and MFs of liver origin.? 2012 Baishideng.All rights reserved.
文摘After the demonstration that somatic cells could be reprogrammed to a pluripotent state,exciting new prospects were opened for the cardiac regeneration field.It did not take long for the development of strategies to convert somatic cells directly into cardiomyocytes.Despite the intrinsic difficulties of cell reprogramming,such as low efficiency,the therapeutic possibilities created by the ability to turn scar into muscle are enormous.Here,we discuss some of the major advances and strategies used in direct cardiac reprogramming and examine discrepancies and concerns that still need to be resolved in the field.
