on August 15, 2005
Published online before print August 15, 2005, doi: 10.1161/CIRCULATIONAHA.104.500447
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Submitted on August 18, 2004
From the Departments of Regenerative Medicine and Tissue Engineering (N.N., T.I., T.I., S.M.), Internal Medicine (N.N., M.Y., K.M.), Biochemistry (K.K., T.T.), and Cardiac Physiology (Y.M., T.F., H.M.), National Cardiovascular Center Research Institute, Osaka; the Cardiovascular Division (M.U.), Kansai Rosai Hospital, Hyogo; the Tissue Engineering Research Center (H.O.), National Institute of Advanced Industrial Science and Technology, Hyogo; and the Department of Cardiovascular Surgery (S.K.), National Cardiovascular Center, Osaka, Japan. * To whom correspondence should be addressed. E-mail: nnagaya{at}ri.ncvc.go.jp.
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.
Revised on April 28, 2005
Accepted on May 10, 2005
Transplantation of Mesenchymal Stem Cells Improves Cardiac Function in a Rat Model of Dilated Cardiomyopathy
Noritoshi Nagaya MD*,
Key words: myocytes • angiogenesis • heart failure • growth substances • transplantation
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