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Am J Physiol Heart Circ Physiol 297: H1606-H1616, 2009. First published September 25, 2009; doi:10.1152/ajpheart.00590.2009
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TRANSLATIONAL PHYSIOLOGY

Allogenic stem cell therapy improves right ventricular function by improving lung pathology in rats with pulmonary hypertension

Soban Umar,1 Yvonne P. de Visser,2 Paul Steendijk,1 Cindy I. Schutte,1 El Houari Laghmani,2 Gerry T. M. Wagenaar,2 Wilhelmina H. Bax,1 Eleni Mantikou,1 Daniel A. Pijnappels,1 Douwe E. Atsma,1 Martin J. Schalij,1 Ernst E. van der Wall,1 and Arnoud van der Laarse1

1Departments of Cardiology and 2Pediatrics, Leiden University Medical Center, Leiden, The Netherlands

Submitted July 1, 2009 ; accepted in final form September 23, 2009

Pulmonary arterial hypertension (PAH) is a chronic lung disease that leads to right ventricular (RV) hypertrophy (RVH), remodeling, and failure. We tested treatment with bone marrow-derived mesenchymal stem cells (MSCs) obtained from donor rats with monocrotaline (MCT)-induced PAH to recipient rats with MCT-induced PAH on pulmonary artery pressure, lung pathology, and RV function. This model was chosen to mimic autologous MSC therapy. On day 1, PAH was induced by MCT (60 mg/kg) in 20 female Wistar rats. On day 14, rats were treated with 106 MSCs intravenously (MCT + MSC) or with saline (MCT60). MSCs were obtained from donor rats with PAH at 28 days after MCT. A control group received saline on days 1 and 14. On day 28, the RV function of recipient rats was assessed, followed by isolation of the lungs and heart. RVH was quantified by the weight ratio of the RV/(left ventricle + interventricular septum). MCT induced an increase of RV peak pressure (from 27 ± 5 to 42 ± 17 mmHg) and RVH (from 0.25 ± 0.04 to 0.47 ± 0.12), depressed the RV ejection fraction (from 56 ± 11 to 43 ± 6%), and increased lung weight (from 0.96 ± 0.15 to 1.66 ± 0.32 g), including thickening of the arteriolar walls and alveolar septa. MSC treatment attenuated PAH (31 ± 4 mmHg) and RVH (0.32 ± 0.07), normalized the RV ejection fraction (52 ± 5%), reduced lung weight (1.16 ± 0.24 g), and inhibited the thickening of the arterioles and alveolar septa. We conclude that the application of MSCs from donor rats with PAH reduces RV pressure overload, RV dysfunction, and lung pathology in recipient rats with PAH. These results suggest that autologous MSC therapy may alleviate cardiac and pulmonary symptoms in PAH patients.

pulmonary arterial hypertension; heart failure; hypertrophy; remodeling; monocrotaline


Address for reprint requests and other correspondence: A. van der Laarse, Dept. of Cardiology, Leiden Univ. Medical Center, PO Box 9600, Leiden 2300 RC, The Netherlands (e-mail: a.van_der_laarse{at}lumc.nl).






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