Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy
Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy
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DOI：
10.1161/circulationaha.104.500447
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发表时间：
2005-08-23
期刊：
影响因子：
37.8
通讯作者：
Kitamura, S
中科院分区：
文献类型：
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作者：
Nagaya, N;Kangawa, K;Kitamura, S
背景-多能间充质干细胞(MSCs)可分化为多种细胞，包括心肌细胞和血管内皮细胞。然而，关于MSC移植对扩张型心肌病(DCM)的治疗效力的信息很少，扩张型心肌病(DCM)是心力衰竭的重要原因。方法和结果-我们研究了移植的MSCs是否在扩张型心肌病大鼠模型中诱导肌肉生成和血管生成，并改善心功能。从同基因成年大鼠骨髓抽提物和体外扩增的大鼠骨髓中分离出MSCs。培养的MSCs分泌大量血管生成、抗凋亡和有丝分裂因子血管内皮生长因子、肝细胞生长因子、肾上腺髓质素和胰岛素样生长因子-1。免疫后5周，心肌内注射MSCs或赋形剂。一些移植的MSCs心脏标志物结蛋白、心肌肌钙蛋白T和连接蛋白-43呈阳性，而另一些则形成血管结构，呈von Willebrand因子或平滑肌肌动蛋白阳性。与载体注射相比，MSC移植显著增加心肌毛细血管密度，降低心肌胶原体积分数，降低左室舒张末压(11+/-1vs16+/-1 mm Hg，P<；0.05)，增加左心室最大dp/dt(6767+/-323vs5138+/-280 mm Hg/S，P<；0.05)。结论：MSC移植可改善DCM模型大鼠的心功能，其机制可能是通过诱导心肌新生和血管生成，抑制心肌纤维化。MSCs的有益作用可能不仅通过分化为心肌细胞和血管细胞来实现，还可能通过它们提供大量血管生成、抗凋亡和有丝分裂因子的能力来实现。
Background - Pluripotent mesenchymal stem cells (MSCs) differentiate into a variety of cells, including cardiomyocytes and vascular endothelial cells. However, little information is available about the therapeutic potency of MSC transplantation in cases of dilated cardiomyopathy (DCM), an important cause of heart failure.Methods and Results - We investigated whether transplanted MSCs induce myogenesis and angiogenesis and improve cardiac function in a rat model of DCM. MSCs were isolated from bone marrow aspirates of isogenic adult rats and expanded ex vivo. Cultured MSCs secreted large amounts of the angiogenic, antiapoptotic, and mitogenic factors vascular endothelial growth factor, hepatocyte growth factor, adrenomedullin, and insulin-like growth factor-1. Five weeks after immunization, MSCs or vehicle was injected into the myocardium. Some engrafted MSCs were positive for the cardiac markers desmin, cardiac troponin T, and connexin-43, whereas others formed vascular structures and were positive for von Willebrand factor or smooth muscle actin. Compared with vehicle injection, MSC transplantation significantly increased capillary density and decreased the collagen volume fraction in the myocardium, resulting in decreased left ventricular end-diastolic pressure (11 +/- 1 versus 16 +/- 1 mm Hg, P < 0.05) and increased left ventricular maximum dP/dt ( 6767 +/- 323 versus 5138 +/- 280 mm Hg/s, P < 0.05).Conclusions - MSC transplantation improved cardiac function in a rat model of DCM, possibly through induction of myogenesis and angiogenesis, as well as by inhibition of myocardial fibrosis. The beneficial effects of MSCs might be mediated not only by their differentiation into cardiomyocytes and vascular cells but also by their ability to supply large amounts of angiogenic, antiapoptotic, and mitogenic factors.