Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice
Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice
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DOI：
10.1073/pnas.0608799103
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发表时间：
2006-11-28
影响因子：
11.1
通讯作者：
Entman, Mark L.
中科院分区：
文献类型：
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作者：
Haudek, Sandra B.;Xia, Ying;Entman, Mark L.
我们以前描述了一种小鼠模型的纤维化缺血/再灌注心肌病（I/RC）所产生的日常，短暂的冠状动脉闭塞。I/RC的一个特点是单核细胞趋化蛋白1（MCP-1）的长期升高，这是专性的表型，并可能有助于血细胞的摄取。在这里，我们描述了在I/RC心脏的一个小的纺锤形成纤维细胞，高度增殖和表达胶原蛋白I和α-平滑肌肌动蛋白（肌成纤维细胞标志物），CD 34（前体标志物），和CD 45（造血标志物）的人口。这些细胞占所有非肌细胞活细胞的3%。为了确认细胞的骨髓来源，通过用来自ROSA 26（表达lacZ的同源系）的骨髓拯救经辐射的C57 BL/6小鼠来创建嵌合小鼠。I/RC导致大量含有lacZ的梭形成纤维细胞。我们假设成纤维细胞前体代表了单核细胞亚群的发育路径，我们已经证明其表型受血清淀粉样蛋白P（SAP）的影响。因此，我们在体内给予SAP，显著减少了增殖的梭形成纤维细胞的数量，并完全防止了I/RC诱导的纤维化和整体心室功能障碍。相比之下，SAP没有抑制I/RC中观察到的炎症或趋化因子表达。SAP是五聚蛋白家族的成员，与Fc γ受体结合并改变单核细胞的病理生理功能。我们的数据表明，SAP干扰假设的成纤维细胞表型的单核细胞的一个子集，SAP可能是一个重要的调节炎症和非适应性纤维化之间的联系在心脏。
We previously described a mouse model of fibrotic ischemia/reperfusion cardiomyopathy (I/RC) arising from daily, brief coronary occlusion. One characteristic of I/RC was the prolonged elevation of monocyte chemoattractant protein 1 (MCP-1), which was obligate to its phenotype and may contribute to the uptake of bloodborne cells. Here we describe in I/RC hearts a population of small spindle-shaped fibroblasts that were highly proliferative and expressed collagen I and a-smooth muscle actin (myofibroblast markers), CD34 (a precursor marker), and CD45 (a hematopoietic marker). These cells represented 3% of all nonmyocyte live cells. To confirm the cells' bone marrow origin, chimeric mice were created by the rescue of irradiated C57BL/6 mice with marrow from ROSA26, a congenic line expressing lacZ. I/RC resulted in a large population of spindle-shaped fibroblasts containing lacZ. We postulated that the fibroblast precursors represented a developmental path for a subset of monocytes, whose phenotype we have shown to be influenced by serum amyloid P (SAP). Thus, we administered SAP in vivo, which markedly reduced the number of proliferative spindle-shaped fibroblasts and completely prevented I/RC-induced fibrosis and global ventricular dysfunction. By contrast, SAP did not suppress the inflammation or chemokine expression seen in I/RC. SAP, a member of the pentraxin family, binds to Fc gamma receptors and modifies the pathophysiological function of monocytes. Our data suggest that SAP interferes with assumption of a fibroblast phenotype in a subset of monocytes and that SAP may be an important regulator in the linkage between inflammation and nonadaptive fibrosis in the heart.