美国格拉德斯通心血管病研究所的科学家宣称,他们首次确定了对培养新生心脏细胞极为关键的遗传因子。相关研究论文发表在的《自然》杂志上。
几十年来,科学家们始终未能确定一种能将非肌细胞转化为心脏肌肉细胞的因子。由贝努瓦·布鲁诺博士带领的研究小组发现,一个由3种基因相互结合而成的结合体可起到这种作用。这是在哺乳动物细胞或组织中,相互结合的基因首次被确定具有促进心脏细胞分裂的功能。
在西方,心脏病已成了导致死亡的一大杀手,在了解如何培养新的细胞来修复受损心脏方面,这项研究将是一个具有重要意义的开端。
这3个因子中的两个是一种被称为转录因子的遗传物质,它们能控制基因与DNA的结合并确定哪种基因的活性被激活。这两种被称为GATA4和TBX5的转录因子,在发生突变后会导致心脏病,同时也会通过相互作用控制其他基因。
当研究人员在小鼠的细胞中加入一种不同的结合体时,这两种转录因子在促进普通细胞转化为心脏细胞的过程中发挥了重要的作用。令人惊讶的是一种被称为BAF60c的心肌特异性蛋白,它能帮助GATA4和TBX5这样的转录因子进入被其改变的DNA区域,起到某种开关的作用。
而这些发现促使布鲁诺小组对BAF60c在心脏细胞分化中的作用进行了新的探索。研究发现,另外的第3个因子能分化为小鼠的中胚层,而中胚层具有被诱导成骨骼、血液、肌肉、心脏以及其他组织的潜力,也可被培养成能使心脏有节奏跳动的心肌细胞。
布鲁诺说,这些因子为控制细胞分化提供了一种强大的机制,这一发现也将有助于人们对心肌细胞进行重新编程,以最终用于临床目的。(生物谷Bioon.com)
生物谷推荐原始出处:
Nature,doi:10.1038/nature08039,Jun K. Takeuchi,Benoit G. Bruneau
Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors
Jun K. Takeuchi1,2 & Benoit G. Bruneau1,3
1 Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA
2 Division of Cardiovascular Research, Global-Edge Institute, Tokyo Institute of Technology, Frontier S2-16, Nagatsuda, Midori-ku, Yokohama, Kanagawa 226-8503, Japan
3 Department of Pediatrics, Cardiovascular Research Institute, and Institute for Regeneration Medicine, University of California, San Francisco, California 94158, USA
Heart disease is the leading cause of mortality and morbidity in the western world. The heart has little regenerative capacity after damage, leading to much interest in understanding the factors required to produce new cardiac myocytes. Despite a robust understanding of the molecular networks regulating cardiac differentiation1, 2, no single transcription factor or combination of factors has been shown to activate the cardiac gene program de novo in mammalian cells or tissues. Here we define the minimal requirements for transdifferentiation of mouse mesoderm to cardiac myocytes. We show that two cardiac transcription factors, Gata4 and Tbx5, and a cardiac-specific subunit of BAF chromatin-remodelling complexes, Baf60c (also called Smarcd3), can direct ectopic differentiation of mouse mesoderm into beating cardiomyocytes, including the normally non-cardiogenic posterior mesoderm and the extraembryonic mesoderm of the amnion. Gata4 with Baf60c initiated ectopic cardiac gene expression. Addition of Tbx5 allowed differentiation into contracting cardiomyocytes and repression of non-cardiac mesodermal genes. Baf60c was essential for the ectopic cardiogenic activity of Gata4 and Tbx5, partly by permitting binding of Gata4 to cardiac genes, indicating a novel instructive role for BAF complexes in tissue-specific regulation. The combined function of these factors establishes a robust mechanism for controlling cellular differentiation, and may allow reprogramming of new cardiomyocytes for regenerative purposes.