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首页> 外文学位 >Glucocorticoid receptor directs cardiogenic mesoderm specification in murine embryonic stem cells by induction of cardiogenic factors in endoderm.
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Glucocorticoid receptor directs cardiogenic mesoderm specification in murine embryonic stem cells by induction of cardiogenic factors in endoderm.

机译：糖皮质激素受体通过诱导内胚层中的心源性因子指导小鼠胚胎干细胞中的心源性中胚层规格。

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摘要

Heart failure is the number one cause of death in the developed world. The progression of the disease leads to the loss of cardiomyocytes that cannot be replaced endogenously. Embryonic stem cells (ESCs) can be differentiated in vitro into cardiomyocytes. The identification of drug-like compounds that can enrich the differentiating ESC cultures with cardiomyocyte progenitors would be beneficial to generate and expand cardiomyocyte cultures for research and clinical applications, while also serving as probes to dissect the mechanisms that control differentiation.;In order to identify novel signaling proteins and pathways involved in cardiogenesis, we developed a fluorescence-based reporter system to screen chemical libraries for cardiomyocyte-inducing molecules. This was screened against a library of known drugs and small molecule pathway modulators. Active compounds included hydrocortisone and the artificial glucocorticoid Dexamethasone (Dex), which induced 10-fold increase in cardiomyocytes, confirmed by an upregulation of cardiac markers Tbx5, MEF2c, cTnt, alphaMhc, as well as the endothelial cell marker CD31. Ligand activated GR seems to upregulate a cascade of events in Foxa2+ definitive endoderm that begins with Hnf4a induction and results in Sox17 -> Cer1 upregulation. Cer1 is a known Nodal inhibitor and has been shown to promote cardiogenesis by locally blocking Nodal in committed cardiac progenitors (Flk1+, MesP1 +) and allowing them to proceed with the cardiac program. Dex does so without affecting mesoendoderm lineage choice.;DHP seems to alter the balance between mesoderm and neurectoderm when added early to the cultures, in a time when mesoendoderm specification occurs. Later, once the mesoendoderm has been established, it promotes cardiogenesis by inhibiting Nodal/Activin signaling at the receptor level by a mechanism yet to be elucidated---recent data suggests this might be receptor type specific. It appears to mimic the effects of the natural cardiac inducer Cer-1 by blocking Nodal/Activin/TGFb- and BMP-signaling both in cardiac progenitors, resulting in an augmentation of the a cardiac restricted Flk1+, MesP1+ progenitor population and ultimately of cardiomyocytes. Our results should contribute to a better understanding of the important cross-talk between endoderm and mesoderm progenitors in the establishment and expansion of a cardiac progenitor population.
机译：心力衰竭是发达国家的头号死因。疾病的进展导致无法内源替代的心肌细胞的丢失。胚胎干细胞（ESCs）可以在体外分化为心肌细胞。鉴定可以用心肌细胞祖细胞丰富分化的ESC培养物的类药物化合物，将有利于生成和扩展用于研究和临床应用的心肌细胞培养物，同时还可以作为探查控制分化机制的探针。新型信号蛋白和参与心脏发生的途径，我们开发了一种基于荧光的报告系统，用于筛选诱导心肌细胞分子的化学文库。针对已知药物和小分子途径调节剂的文库进行筛选。活性化合物包括氢化可的松和人造糖皮质激素地塞米松（Dex），它们可诱导心肌细胞增加10倍的增加，这通过心脏标志物Tbx5，MEF2c，cTnt，alphaMhc和内皮细胞标志物CD31的上调来证实。配体激活的GR似乎上调Foxa2 +定形内胚层中的一系列事件，这些事件始于Hnf4a诱导，并导致Sox17-> Cer1上调。 Cer1是已知的Nodal抑制剂，并且已显示出通过在定型的心脏祖细胞（Flk1 +，MesP1 +）中局部阻断Nodal并允许他们进行心脏程序来促进心脏发生。 Dex这样做不会影响中胚层的血统选择。在中胚层规格出现的早期，DHP似乎会改变中胚层和中胚层之间的平衡。后来，中胚层一旦建立，它会通过尚待阐明的机制在受体水平上抑制Nodal / Activin信号传导来促进心脏发生-最近的数据表明这可能是受体类型特异性的。它似乎通过阻断心脏祖细胞中的Nodal / Activin / TGFb-和BMP信号来模仿天然心脏诱导物Cer-1的作用，从而导致受心脏限制的Flk1 +，MesP1 +祖细胞以及最终心肌细胞的数量增加。我们的结果应有助于更好地了解内胚层和中胚层祖细胞之间重要的相互影响，以建立和扩大心脏祖细胞群。

著录项

  • 作者

    Cabral Teixeira, Joaquim Miguel.;

  • 作者单位

    University of California, San Diego.;

  • 授予单位 University of California, San Diego.;
  • 学科 Biology Molecular.;Health Sciences Human Development.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 127 p.
  • 总页数 127
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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