Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, Graz, Austria.
J Am Coll Cardiol. 2012 Mar 13;59(11):1008-16. doi: 10.1016/j.jacc.2011.11.036.
The aim of our study was to determine the origin of collagen in the progression of myocardial fibrosis in human adult transplanted hearts.
Changes in the cardiac interstitial collagen network are thought to contribute to abnormal stiffness and function of the myocardium. The origin of fibrosis-mediating fibroblasts remains incompletely understood, and conflicting data from animal models suggest that they are either derived intracardially or immigrate from extracardiac sources.
We studied endomyocardial biopsy specimens from 7 sex-mismatched (female donor heart to a male recipient) heart transplant recipients by a combination of chromogen in situ hybridization using probes specific for Y chromosomes with immunohistochemistry. On the basis of differences in genetic polymorphisms in the type III collagen gene between donor and recipient tissue, we quantitatively determined origin-specific type III collagen gene expression in fibrotic areas containing fibroblasts of putative extracardiac origin.
In areas of increased cardiac fibrosis years after heart transplantation, a substantial number of Y chromosome-positive spindle-shaped cells with a fibroblast-like appearance were detected. Many of these cells were identified as macrophages, and measurement of origin-specific type III collagen synthesis identified cells of intracardiac origin as the main source for collagen turnover in human cardiac fibrosis.
Our data suggest that, in human myocardium, cardiac fibrosis due to chronic allograft rejection up to 15 years after transplantation or scar formation provoked by mechanical trauma is mainly driven by fibroblasts of intracardiac origin. Antifibrotic treatment strategies, therefore, should target molecular mechanisms that induce fibrillogenesis of cells with intracardiac origin.
我们研究的目的是确定在人类成年移植心脏心肌纤维化进展中胶原的来源。
心脏间质胶原网络的变化被认为有助于心肌的异常僵硬和功能。纤维化中介成纤维细胞的来源仍不完全清楚，动物模型的矛盾数据表明它们要么来源于心脏内，要么从心脏外来源迁移而来。
我们通过使用针对 Y 染色体的探针进行原位杂交与免疫组织化学相结合，研究了 7 例性别不匹配（女性供体心脏至男性受体）心脏移植受者的心内膜心肌活检标本。基于供体和受体组织中 III 型胶原基因的遗传多态性差异，我们定量确定了纤维化区域中具有推测性心脏外来源的成纤维细胞的起源特异性 III 型胶原基因表达。
在心脏移植后多年的心脏纤维化区域中，检测到大量具有成纤维细胞样外观的 Y 染色体阳性梭形细胞。这些细胞中的许多被鉴定为巨噬细胞，并且起源特异性 III 型胶原合成的测量确定了心脏内起源的细胞是人类心脏纤维化中胶原周转的主要来源。
我们的数据表明，在人类心肌中，慢性同种异体移植排斥引起的心肌纤维化（移植后长达 15 年）或机械创伤引起的瘢痕形成主要由心脏内起源的成纤维细胞驱动。因此，抗纤维化治疗策略应针对诱导具有心脏内起源的细胞纤维生成的分子机制。
