Skin deep: what can the study of dermal fibroblasts teach us about dilated cardiomyopathy?
Skin deep: what can the study of dermal fibroblasts teach us about dilated cardiomyopathy?
复制标题
深入浅出：真皮成纤维细胞的研究可以告诉我们有关扩张型心肌病的什么信息？
DOI：
10.1016/j.yjmcc.2009.11.021
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发表时间：
2010
影响因子：
5
通讯作者：
Jensen,BrianC
中科院分区：
文献类型：
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作者：
Jensen,BrianC
人类心脏组织很难获得。它的采购取决于能否进入心脏移植或心室辅助装置移植的中心，以及是否愿意在非正常时间和短时间内为科学服务。似乎这些障碍还不足以让潜在的翻译研究者感到沮丧，但在分离、培养和研究人类心肌细胞方面存在着具体而棘手的挑战。即使是在精心采购的人类心肌和心肌细胞中进行的观察也受到限制，正如该杂志先前发表的一篇深思熟虑的评论所概述的那样。[1]因此，心血管研究界在很大程度上依赖于动物模型来研究心肌疾病，其中最常见的是基因改变的小鼠。这些模型通常确实准确地预测了人类生物学，但测试其固有的假设是至关重要的，并且仍然是生物医学研究企业的核心。在这方面，人类心脏组织的可用性是忠实翻译的一个重要限速步骤，需要新的方法来研究人类心肌生物学。家族性扩张型心肌病（DCM）似乎特别适合使用基因改变的小鼠模型来阐明细胞机制，因为这种疾病几乎总是由单一突变引起，并且由于从人类先证者获得心肌细胞的上述困难。家族性扩张型心肌病曾经被认为是罕见的，现在似乎占所有特发性扩张型心肌病的20 - 50%，[2]这是50%的心脏移植手术的基础诊断。[3]超过20个基因与家族性DCM有关，[4]其中大多数编码参与力的产生或传递的肌节或细胞骨架蛋白。[5]也就是说，在细胞水平上，家族性扩张型心肌病在很大程度上被认为是一种细胞产生力的疾病，对这种疾病的细胞生物学研究几乎完全集中在心肌细胞上，这是一种独特的心肌细胞类型。
Human heart tissue is difficult to obtain. Its procurement depends upon access to a center at which heart transplants or ventricular assist device implantations occur, as well as a willingness to serve science at odd hours and on short notice. As if these barriers weren’t sufficiently discouraging to the would-be translational investigator, there are specific and thorny challenges associated with isolating, culturing, and studying human cardiomyocytes. Even observations made in meticulously procured human myocardium and cardiomyocytes are subject to limitations, as outlined in a thoughtful review published previously in this journal.[1] Thus the cardiovascular research community relies largely upon animal models to study myocardial disease, the most common of which is the genetically altered mouse. Such models often do predict human biology accurately, however testing their inherent assumptions is undeniably important and remains central to the biomedical research enterprise. In this regard, the availability of human heart tissue stands as one significant ratelimiting step in faithful translation, and novel approaches to the investigation of human myocardial biology are needed.Familial dilated cardiomyopathy (DCM) seems particularly well suited to the use of genetically altered mouse models for elucidation of cellular mechanism, both because the disorder almost always arises from a single mutation, and because of the aforementioned difficulties in obtaining cardiomyocytes from the human proband. Once thought to be rare, familial DCM now appears to constitute 20–50% of all idiopathic DCM,[2] which is the underlying diagnosis in 50% of all heart transplants.[3] More than twenty genes have been implicated in familial DCM,[4] the majority of which encode sarcomeric or cytoskeletal proteins that are involved in the generation or transmission of force.[5] That is to say that on a cellular level, familial DCM has been understood largely as a disease of forcegenerating cells, and investigation of the cellular biology of this disorder has focused almost entirely on the cardiomyocyte, that uniquely cardiac cell type.