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Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts

Nature Medicine volume 9, pages 1195–1201 (2003)Cite this article

Abstract

Transplantation of adult bone marrow–derived mesenchymal stem cells has been proposed as a strategy for cardiac repair following myocardial damage. However, poor cell viability associated with transplantation has limited the reparative capacity of these cells in vivo. In this study, we genetically engineered rat mesenchymal stem cells using ex vivo retroviral transduction to overexpress the prosurvival gene Akt1 (encoding the Akt protein). Transplantation of 5 × 106 cells overexpressing Akt into the ischemic rat myocardium inhibited the process of cardiac remodeling by reducing intramyocardial inflammation, collagen deposition and cardiac myocyte hypertrophy, regenerated 80–90% of lost myocardial volume, and completely normalized systolic and diastolic cardiac function. These observed effects were dose (cell number) dependent. Mesenchymal stem cells transduced with Akt1 restored fourfold greater myocardial volume than equal numbers of cells transduced with the reporter gene lacZ. Thus, mesenchymal stem cells genetically enhanced with Akt1 can repair infarcted myocardium, prevent remodeling and nearly normalize cardiac performance.

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Figure 1: Immunocytochemical characterization of MSCs.
Figure 2: Effect of Akt1 transduction in MSC.
Figure 3: Analysis of myocardial repair 3 weeks after MSC injection into ischemic rat hearts.
Figure 4: Injection of MSCs into ischemic rat heart reduced infarct volume.
Figure 5: MSC injection improved cardiac function.
Figure 6: Injection of MSCs inhibits ventricular remodeling.

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Acknowledgements

We thank D.G. Phinney, D.J. Prockop and R. Pratt for helpful discussions and assistance in establishing culture conditions for propagation of bone marrow–derived MSCs; M.A. Perrella for sharing Akt1 constructs and for helpful discussions on Akt biology; and S. Colgan for the use of a hypoxia chamber. This work was supported by grants HL35610 (V.J.D.), HL058516 (V.J.D.), HL072010 (V.J.D.), HL073219 (V.J.D.) and HL52320 (J.S.I.) from the National Heart, Lung and Blood Institute, US National Institutes of Health. A.A.M. is the recipient of a National Research Service Award (1 F32 NHL 10503-01) from the National Heart, Lung and Blood Institute, National Institutes of Health; and the Robert R. Linton Research Fellowship from the Department of Surgery, Massachusetts General Hospital. N.N. is a recipient of a scholarship from the Canadian Institutes of Health Research. M.R. is the recipient of an American Heart Association Research Award (0120195T).

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  1. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, 02115, Massachusetts, USA

    Abeel A Mangi, Nicolas Noiseux, Deling Kong, Huamei He, Mojgan Rezvani, Joanne S Ingwall & Victor J Dzau

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  1. Abeel A Mangi
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Correspondence to Victor J Dzau.

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Mangi, A., Noiseux, N., Kong, D. et al. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med 9, 1195–1201 (2003). https://doi.org/10.1038/nm912

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