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(Circulation. 2007;116:1176-1184.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

Bone Marrow–Derived Cells Are Involved in the Pathogenesis of Cardiac Hypertrophy in Response to Pressure Overload

Jin Endo, MD; Motoaki Sano, MD, PhD; Jun Fujita, MD, PhD; Kentaro Hayashida, MD, PhD; Shinsuke Yuasa, MD, PhD; Naoki Aoyama, MS; Yuji Takehara, MD, PhD; Osamu Kato, MD, PhD; Shinji Makino, MD, PhD; Satoshi Ogawa, MD, PhD; Keiichi Fukuda, MD, PhD

From the Department of Regenerative Medicine and Advanced Cardiac Therapeutics (J.E., M.S., J.F., K.H., S.Y., S.M., K.F.), Cardiology Division (J.E., J.F., K.H., S.O.), Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan, and Advanced Medical Research Institute of Fertility (N.A., Y.T., O.K.), Kato Lady’s Clinic, Tokyo, Japan.

Correspondence to Dr Keiichi Fukuda, Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan. E-mail kfukuda{at}sc.itc.keio.ac.jp

Received July 10, 2006; accepted June 15, 2007.

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 -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 -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.

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