Bone marrow-derived cells are involved in the pathogenesis of cardiac hypertrophy in response to pressure overload
Bone marrow-derived cells are involved in the pathogenesis of cardiac hypertrophy in response to pressure overload
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DOI：
10.1161/circulationaha.106.650903
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发表时间：
2007-09-04
期刊：
影响因子：
37.8
通讯作者：
Fukuda, Keiichi
中科院分区：
文献类型：
--
作者：
Endo, Jin;Sano, Motoaki;Fukuda, Keiichi
背景-骨髓(BM)细胞具有广泛的分化潜能，可以根据病理生理信号形成不同的细胞系。本研究探讨骨髓来源的细胞是否参与心肌肥大的发病机制，并探讨其可能的细胞机制。方法与结果：将绿色荧光蛋白转基因小鼠的骨髓细胞移植到受到致死照射的野生型小鼠体内。嵌合的小鼠要么长期缺氧，要么横断性主动脉收缩。骨髓来源的增强型绿色荧光蛋白表达的心肌细胞的数量随着时间的推移而增加，主要出现在压力超负荷的心室肌中，尽管它们占受体心肌细胞的0.01%。为了确定BM来源的心肌细胞是来自细胞融合还是在单细胞水平上的转分化，将来自双条件Cre报告小鼠Z/EG的BM细胞移植到致死照射的Cre小鼠。骨髓来源的心肌细胞既有细胞融合的来源，也有转分化的来源。有趣的是，表达波形蛋白和α-平滑肌肌动蛋白的骨髓来源的肌成纤维细胞集中在血管周围纤维化区。这些细胞最初表达MAC-1/CD14，但在慢性期失去了这些标志物的表达，这表明它们来自单核细胞。在培养的人单核细胞中也存在类似的现象，大多数单核细胞最终表达波形蛋白和α-平滑肌肌动蛋白。结论-我们发现骨髓来源的细胞通过细胞融合和转分化的双重机制参与了心肌肥厚的发病。此外，本研究结果提示，BM来源的单核细胞聚集在血管周围间隙，可能通过直接分化为肌成纤维细胞在血管周围纤维化的形成中发挥重要作用。
Background-Bone marrow ( BM) cells possess broad differentiation potential and can form various cell lineages in response to pathophysiological cues. The present study investigated whether BM-derived cells contribute to the pathogenesis of cardiac hypertrophy, as well as the possible cellular mechanisms involved in such a role.Methods and Results-Lethally irradiated wild-type mice were transplanted with BM cells from enhanced green fluorescent protein-transgenic mice. The chimeric mice were subjected to either prolonged hypoxia or transverse aortic constriction. BM-derived enhanced green fluorescent protein-expressing cardiomyocytes increased in number over time, emerging predominantly in the pressure-overloaded ventricular myocardium, although they constituted < 0.01% of recipient cardiomyocytes. To determine whether BM-derived cardiomyocytes were derived from cell fusion or transdifferentiation at the single-cell level, lethally irradiated Cre mice were transplanted with BM cells from the double-conditional Cre reporter mouse line Z/EG. BM-derived cardiomyocytes were shown to arise from both cell fusion and transdifferentiation. Interestingly, BM-derived myofibroblasts expressing both vimentin and alpha-smooth muscle actin were concentrated in the perivascular fibrotic area. These cells initially expressed MAC-1/CD14 but lost expression of these markers during the chronic phase, which suggests that they were derived from monocytes. A similar phenomenon occurred in cultured human monocytes, most of which ultimately expressed vimentin and alpha-smooth muscle actin.Conclusions-We found that BM-derived cells were involved in the pathogenesis of cardiac hypertrophy via the dual mechanisms of cell fusion and transdifferentiation. Moreover, the present results suggest that BM-derived monocytes accumulating in the perivascular space might play an important role in the formation of perivascular fibrosis via direct differentiation into myofibroblasts.