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1.
Circ Res ; 102(5): 597-606, 2008 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-18202313

RESUMO

Heart failure is the leading cause of death in the elderly, but whether this is the result of a primary aging myopathy dictated by depletion of the cardiac progenitor cell (CPC) pool is unknown. Similarly, whether current lifespan reflects the ineluctable genetic clock or heart failure interferes with the genetically determined fate of the organ and organism is an important question. We have identified that chronological age leads to telomeric shortening in CPCs, which by necessity generate a differentiated progeny that rapidly acquires the senescent phenotype conditioning organ aging. CPC aging is mediated by attenuation of the insulin-like growth factor-1/insulin-like growth factor-1 receptor and hepatocyte growth factor/c-Met systems, which do not counteract any longer the CPC renin-angiotensin system, resulting in cellular senescence, growth arrest, and apoptosis. However, pulse-chase 5-bromodeoxyuridine-labeling assay revealed that the senescent heart contains functionally competent CPCs that have the properties of stem cells. This subset of telomerase-competent CPCs have long telomeres and, following activation, migrate to the regions of damage, where they generate a population of young cardiomyocytes, reversing partly the aging myopathy. The senescent heart phenotype and heart failure are corrected to some extent, leading to prolongation of maximum lifespan.


Assuntos
Células-Tronco Adultas/efeitos dos fármacos , Envelhecimento/efeitos dos fármacos , Insuficiência Cardíaca/terapia , Fator de Crescimento de Hepatócito/uso terapêutico , Fator de Crescimento Insulin-Like I/uso terapêutico , Miócitos Cardíacos/efeitos dos fármacos , Células-Tronco Adultas/metabolismo , Células-Tronco Adultas/patologia , Envelhecimento/patologia , Animais , Antígenos de Diferenciação/biossíntese , Apoptose/efeitos dos fármacos , Contagem de Células , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Inibidor p16 de Quinase Dependente de Ciclina/biossíntese , Modelos Animais de Doenças , Vias de Administração de Medicamentos , Coração/efeitos dos fármacos , Coração/crescimento & desenvolvimento , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Masculino , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fenótipo , Ratos , Ratos Endogâmicos F344 , Receptores de Fatores de Crescimento/metabolismo , Regeneração/efeitos dos fármacos , Taxa de Sobrevida , Telômero/metabolismo
2.
Circ Res ; 97(7): 663-73, 2005 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-16141414

RESUMO

Cardiac stem cells and early committed cells (CSCs-ECCs) express c-Met and insulin-like growth factor-1 (IGF-1) receptors and synthesize and secrete the corresponding ligands, hepatocyte growth factor (HGF) and IGF-1. HGF mobilizes CSCs-ECCs and IGF-1 promotes their survival and proliferation. Therefore, HGF and IGF-1 were injected in the hearts of infarcted mice to favor, respectively, the translocation of CSCs-ECCs from the surrounding myocardium to the dead tissue and the viability and growth of these cells within the damaged area. To facilitate migration and homing of CSCs-ECCs to the infarct, a growth factor gradient was introduced between the site of storage of primitive cells in the atria and the region bordering the infarct. The newly-formed myocardium contained arterioles, capillaries, and functionally competent myocytes that with time increased in size, improving ventricular performance at healing and long thereafter. The volume of regenerated myocytes was 2200 microm3 at 16 days after treatment and reached 5100 microm3 at 4 months. In this interval, nearly 20% of myocytes reached the adult phenotype, varying in size from 10,000 to 20,000 microm3. Moreover, there were 43+/-13 arterioles and 155+/-48 capillaries/mm2 myocardium at 16 days, and 31+/-6 arterioles and 390+/-56 capillaries at 4 months. Myocardial regeneration induced increased survival and rescued animals with infarcts that were up to 86% of the ventricle, which are commonly fatal. In conclusion, the heart has an endogenous reserve of CSCs-ECCs that can be activated to reconstitute dead myocardium and recover cardiac function.


Assuntos
Fator de Crescimento de Hepatócito/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , Infarto do Miocárdio/terapia , Miocárdio/citologia , Proteínas Proto-Oncogênicas c-met/fisiologia , Receptor IGF Tipo 1/fisiologia , Regeneração , Células-Tronco/fisiologia , Função Ventricular , Animais , Fusão Celular , Movimento Celular/efeitos dos fármacos , Circulação Coronária , Camundongos , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/fisiologia , Transdução de Sinais
3.
Cell ; 114(6): 763-76, 2003 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-14505575

RESUMO

The notion of the adult heart as terminally differentiated organ without self-renewal potential has been undermined by the existence of a subpopulation of replicating myocytes in normal and pathological states. The origin and significance of these cells has remained obscure for lack of a proper biological context. We report the existence of Lin(-) c-kit(POS) cells with the properties of cardiac stem cells. They are self-renewing, clonogenic, and multipotent, giving rise to myocytes, smooth muscle, and endothelial cells. When injected into an ischemic heart, these cells or their clonal progeny reconstitute well-differentiated myocardium, formed by blood-carrying new vessels and myocytes with the characteristics of young cells, encompassing approximately 70% of the ventricle. Thus, the adult heart, like the brain, is mainly composed of terminally differentiated cells, but is not a terminally differentiated organ because it contains stem cells supporting its regeneration. The existence of these cells opens new opportunities for myocardial repair.


Assuntos
Diferenciação Celular/fisiologia , Coração/fisiologia , Células-Tronco Multipotentes/citologia , Miocárdio/citologia , Miócitos Cardíacos/citologia , Regeneração/fisiologia , Animais , Biomarcadores , Vasos Sanguíneos/citologia , Vasos Sanguíneos/crescimento & desenvolvimento , Linhagem da Célula/fisiologia , Células Cultivadas , Células Clonais/citologia , Células Clonais/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Feminino , Células-Tronco Multipotentes/metabolismo , Células-Tronco Multipotentes/transplante , Infarto do Miocárdio/terapia , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Ratos , Ratos Endogâmicos F344
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