Endo Jin, Sano Motoaki, Fujita Jun, Hayashida Kentaro, Yuasa Shinsuke, Aoyama Naoki, Takehara Yuji, Kato Osamu, Makino Shinji, Ogawa Satoshi, Fukuda Keiichi
Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan.
Circulation. 2007 Sep 4;116(10):1176-84. doi: 10.1161/CIRCULATIONAHA.106.650903. Epub 2007 Aug 13.
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.
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.
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.
骨髓（BM）细胞具有广泛的分化潜能，可根据病理生理信号形成各种细胞谱系。本研究调查了骨髓来源的细胞是否参与心脏肥大的发病机制，以及参与这一作用的可能细胞机制。
对经致死剂量照射的野生型小鼠移植来自增强型绿色荧光蛋白转基因小鼠的骨髓细胞。将嵌合小鼠置于长时间缺氧环境或进行主动脉缩窄手术。随着时间推移，骨髓来源的表达增强型绿色荧光蛋白的心肌细胞数量增加，主要出现在压力超负荷的心室心肌中，尽管它们在受体心肌细胞中所占比例不到0.01%。为了确定骨髓来源的心肌细胞是源自细胞融合还是单细胞水平的转分化，对经致死剂量照射的Cre小鼠移植来自双条件Cre报告基因小鼠品系Z/EG的骨髓细胞。结果显示骨髓来源的心肌细胞既源自细胞融合也源自转分化。有趣的是，同时表达波形蛋白和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域。这些细胞最初表达MAC-1/CD14，但在慢性期失去这些标志物的表达，这表明它们源自单核细胞。在培养的人单核细胞中也出现了类似现象，其中大多数最终表达波形蛋白和α-平滑肌肌动蛋白。
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心脏肥大的发病机制。此外，本研究结果表明，在血管周围空间积聚的骨髓来源的单核细胞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。
