Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Circulation ; 132(2): 109-21, 2015 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-25995316

RESUMO

BACKGROUND: Heart development is tightly regulated by signaling events acting on a defined number of progenitor and differentiated cardiac cells. Although loss of function of these signaling pathways leads to congenital malformation, the consequences of cardiac progenitor cell or embryonic cardiomyocyte loss are less clear. In this study, we tested the hypothesis that embryonic mouse hearts exhibit a robust mechanism for regeneration after extensive cell loss. METHODS AND RESULTS: By combining a conditional cell ablation approach with a novel blastocyst complementation strategy, we generated murine embryos that exhibit a full spectrum of cardiac progenitor cell or cardiomyocyte ablation. Remarkably, ablation of up to 60% of cardiac progenitor cells at embryonic day 7.5 was well tolerated and permitted embryo survival. Ablation of embryonic cardiomyocytes to a similar degree (50% to 60%) at embryonic day 9.0 could be fully rescued by residual myocytes with no obvious adult cardiac functional deficit. In both ablation models, an increase in cardiomyocyte proliferation rate was detected and accounted for at least some of the rapid recovery of myocardial cellularity and heart size. CONCLUSION: Our study defines the threshold for cell loss in the embryonic mammalian heart and reveals a robust cardiomyocyte compensatory response that sustains normal fetal development.


Assuntos
Proliferação de Células/fisiologia , Células-Tronco Embrionárias/fisiologia , Coração Fetal/citologia , Miócitos Cardíacos/fisiologia , Animais , Contagem de Células/métodos , Coração Fetal/crescimento & desenvolvimento , Técnicas de Introdução de Genes , Camundongos , Camundongos Transgênicos
2.
Stem Cells ; 32(6): 1493-502, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24496962

RESUMO

A thorough understanding of the developmental signals that direct pluripotent stem cells (PSCs) toward a cardiac fate is essential for translational applications in disease modeling and therapy. We screened a panel of 44 cytokines/signaling molecules for their ability to enhance Nkx2.5(+) cardiac progenitor cell (CPC) formation during in vitro embryonic stem cell (ESC) differentiation. Treatment of murine ESCs with insulin or insulin-like growth factors (IGF1/2) during early differentiation increased mesodermal cell proliferation and, consequently, CPC formation. Furthermore, we show that downstream mediators of IGF signaling (e.g., phospho-Akt and mTOR) are required for this effect. These data support a novel role for IGF family ligands to expand the developing mesoderm and promote cardiac differentiation. Insulin or IGF treatment could provide an effective strategy to increase the PSC-based generation of CPCs and cardiomyocytes for applications in regenerative medicine.


Assuntos
Linhagem da Célula/efeitos dos fármacos , Fator de Crescimento Insulin-Like II/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , Mesoderma/citologia , Miocárdio/citologia , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células-Tronco Embrionárias/metabolismo , Proteínas Fetais/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Insulina , Mesoderma/efeitos dos fármacos , Mesoderma/embriologia , Mesoderma/metabolismo , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Proteínas com Domínio T/metabolismo , Serina-Treonina Quinases TOR/metabolismo
3.
Circ Res ; 112(6): 900-10, 2013 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-23307821

RESUMO

RATIONALE: Cardiogenesis is regulated by a complex interplay between transcription factors. However, little is known about how these interactions regulate the transition from mesodermal precursors to cardiac progenitor cells (CPCs). OBJECTIVE: To identify novel regulators of mesodermal cardiac lineage commitment. METHODS AND RESULTS: We performed a bioinformatic-based transcription factor binding site analysis on upstream promoter regions of genes that are enriched in embryonic stem cell-derived CPCs. From 32 candidate transcription factors screened, we found that Yin Yang 1 (YY1), a repressor of sarcomeric gene expression, is present in CPCs in vivo. Interestingly, we uncovered the ability of YY1 to transcriptionally activate Nkx2.5, a key marker of early cardiogenic commitment. YY1 regulates Nkx2.5 expression via a 2.1-kb cardiac-specific enhancer as demonstrated by in vitro luciferase-based assays, in vivo chromatin immunoprecipitation, and genome-wide sequencing analysis. Furthermore, the ability of YY1 to activate Nkx2.5 expression depends on its cooperative interaction with Gata4 at a nearby chromatin. Cardiac mesoderm-specific loss-of-function of YY1 resulted in early embryonic lethality. This was corroborated in vitro by embryonic stem cell-based assays in which we showed that the overexpression of YY1 enhanced the cardiogenic differentiation of embryonic stem cells into CPCs. CONCLUSIONS: These results demonstrate an essential and unexpected role for YY1 to promote cardiogenesis as a transcriptional activator of Nkx2.5 and other CPC-enriched genes.


Assuntos
Diferenciação Celular/fisiologia , Células-Tronco Embrionárias/citologia , Proteínas de Homeodomínio/metabolismo , Mioblastos Cardíacos/citologia , Fatores de Transcrição/metabolismo , Fator de Transcrição YY1/fisiologia , Animais , Diferenciação Celular/genética , Fator de Transcrição GATA4/metabolismo , Estudo de Associação Genômica Ampla/métodos , Proteína Homeobox Nkx-2.5 , Camundongos , Mioblastos Cardíacos/química , Ativação Transcricional/fisiologia , Fator de Transcrição YY1/análise , Fator de Transcrição YY1/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...