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1.
Cell Rep ; 23(7): 2168-2174, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29768213

RESUMO

Understanding the mechanisms that control human cardiomyocyte proliferation might be applicable to regenerative medicine. We screened a whole genome collection of human miRNAs, identifying 96 to be capable of increasing proliferation (DNA synthesis and cytokinesis) of human iPSC-derived cardiomyocytes. Chemical screening and computational approaches indicated that most of these miRNAs (67) target different components of the Hippo pathway and that their activity depends on the nuclear translocation of the Hippo transcriptional effector YAP. 53 of the 67 miRNAs are present in human iPSC cardiomyocytes, yet anti-miRNA screening revealed that none are individually essential for basal proliferation of hiPSC cardiomyocytes despite the importance of YAP for proliferation. We propose a model in which multiple endogenous miRNAs redundantly suppress Hippo signaling to sustain the cell cycle of immature cardiomyocytes.


Assuntos
MicroRNAs/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Divisão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , DNA/biossíntese , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , MicroRNAs/genética , Miócitos Cardíacos/efeitos dos fármacos
2.
Nature ; 525(7570): 479-85, 2015 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-26375005

RESUMO

The elucidation of factors that activate the regeneration of the adult mammalian heart is of major scientific and therapeutic importance. Here we found that epicardial cells contain a potent cardiogenic activity identified as follistatin-like 1 (Fstl1). Epicardial Fstl1 declines following myocardial infarction and is replaced by myocardial expression. Myocardial Fstl1 does not promote regeneration, either basally or upon transgenic overexpression. Application of the human Fstl1 protein (FSTL1) via an epicardial patch stimulates cell cycle entry and division of pre-existing cardiomyocytes, improving cardiac function and survival in mouse and swine models of myocardial infarction. The data suggest that the loss of epicardial FSTL1 is a maladaptive response to injury, and that its restoration would be an effective way to reverse myocardial death and remodelling following myocardial infarction in humans.


Assuntos
Proteínas Relacionadas à Folistatina/metabolismo , Miocárdio/metabolismo , Pericárdio/crescimento & desenvolvimento , Pericárdio/metabolismo , Regeneração , Animais , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Feminino , Proteínas Relacionadas à Folistatina/genética , Humanos , Masculino , Camundongos , Mioblastos Cardíacos/citologia , Mioblastos Cardíacos/efeitos dos fármacos , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Pericárdio/citologia , Pericárdio/efeitos dos fármacos , Ratos , Regeneração/efeitos dos fármacos , Transdução de Sinais , Suínos , Transgenes/genética
3.
Cardiovasc Res ; 107(2): 287-94, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-26054850

RESUMO

AIM: Age and injury cause structural and functional changes in coronary artery smooth muscle cells (caSMCs) that influence the pathogenesis of coronary artery disease. Although paracrine signalling is widely believed to drive phenotypic changes in caSMCs, here we show that developmental origin within the fetal epicardium can have a profound effect as well. METHODS AND RESULTS: Fluorescent dye and transgene pulse-labelling techniques in mice revealed that the majority of caSMCs are derived from Wt1(+), Gata5-Cre(+) cells that migrate before E12.5, whereas a minority of cells are derived from a later-emigrating, Wt1(+), Gata5-Cre(-) population. We functionally evaluated the influence of early emigrating cells on coronary artery development and disease by Gata5-Cre excision of Rbpj, which prevents their contribution to coronary artery smooth muscle cells. Ablation of the Gata5-Cre(+) population resulted in coronary arteries consisting solely of Gata5-Cre(-) caSMCs. These coronary arteries appeared normal into early adulthood; however, by 5-8 months of age, they became progressively fibrotic, lost the adventitial outer elastin layer, were dysfunctional and leaky, and animals showed early mortality. CONCLUSION: Taken together, these data reveal heterogeneity in the fetal epicardium that is linked to coronary artery integrity, and that distortion of the coronaries epicardial origin predisposes to adult onset disease.


Assuntos
Doença da Artéria Coronariana/patologia , Miócitos de Músculo Liso/citologia , Pericárdio/patologia , Envelhecimento , Animais , Diferenciação Celular/fisiologia , Camundongos Transgênicos , Músculo Liso Vascular/embriologia , Músculo Liso Vascular/crescimento & desenvolvimento , Pericárdio/embriologia
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