Therapeutic effects of mesenchymal stem cell-derived microvesicles on pulmonary arterial hypertension in rats
Abstract
Jian-ying CHEN1, #, *, Ran AN1, #, Zhen-jun LIU1, #, Jin-ju WANG2, Shu-zhen CHEN2, Mian-ming HONG1, Jing-hu LIU1, Meng-yuan XIAO1, Yan-fang CHEN2, *
1Department of Cardiology, the Affiliated Hospital of Guangdong Medical College, Zhanjiang 524001, China; 2Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA
Aim: Microvesicles (MVs) are nanoscale membrane fragments released from virtually all cell types upon activation or apoptosis, and may contribute to the beneficial effects of stem cell therapy. In this study, we investigated the therapeutic effects of mesenchymal stem cell (MSC) derived MVs (MSC-MVs) on pulmonary artery hypertension (PAH) in rats.
Methods: MSC-MVs were isolated from rat bone marrow MSCs that were cultured in a serum-free conditioned medium. Transmission electron microscopy (TEM), flow cytometry and nanoparticle tracking analysis (NTA) were used to characterize the MVs. Adult SD rats were injected with monocrotaline (50 mg/kg, sc) to induce PAH. Three weeks later, the rats were intravenously injected with MSCs, MSC-MVs or saline for 2 weeks. At the end of treatments, the hemodynamic parameters and pathological right ventricular and pulmonary arterial remodeling were analyzed in each group.
Results: The MSC-MVs showed general morphologic characteristics of MVs and expressed annexin V and CD29 markers under TEM, and their size ranged from 40 to 300 nm. Intravenous injection of MSC-MVs or MSCs significantly ameliorated the mean pulmonary artery pressure (mPAP) and mean right ventricle pressure (mRVP) in PAH rats. Furthermore, intravenous injection of MSC-MVs or MSCs significantly decreased the right ventricle (RV) hypertrophy and pulmonary arteriole area index (AI) and thickness index (TI) in PAH rats.
Conclusion: Intravenous injection of MSC-MVs or MSCs produces similar beneficial effects for treating PAH, and our results provide a basis for cell-free approach in stem cell therapy.
Keywords: stem cell therapy; bone marrow mesenchymal stem cell; microvesicle; pulmonary artery hypertension; chronic heart disease
This work was supported by the National Heart, Lung, and Blood Institute (HL-098637 to Yan-fang CHEN), National Natural Science Foundation of China (81370242 and 81270195), Guangdong Natural Science Foundation (S2013010015005), Science and Technology Planning Project of Guangdong Province (2012B031800224 and 2011B031800249), and Science and Technology Innovation Fund of Guangdong Medical College (STIF201128).
# These authors contributed equally to this work.
* To whom correspondence should be addressed.
E-mail yanfang.chen@wright.edu (Yan-fang CHEN); jychen271@126.com (Jian-ying CHEN)
Received 2014-01-02 Accepted 2014-05-26
Keywords:
1Department of Cardiology, the Affiliated Hospital of Guangdong Medical College, Zhanjiang 524001, China; 2Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA
Aim: Microvesicles (MVs) are nanoscale membrane fragments released from virtually all cell types upon activation or apoptosis, and may contribute to the beneficial effects of stem cell therapy. In this study, we investigated the therapeutic effects of mesenchymal stem cell (MSC) derived MVs (MSC-MVs) on pulmonary artery hypertension (PAH) in rats.
Methods: MSC-MVs were isolated from rat bone marrow MSCs that were cultured in a serum-free conditioned medium. Transmission electron microscopy (TEM), flow cytometry and nanoparticle tracking analysis (NTA) were used to characterize the MVs. Adult SD rats were injected with monocrotaline (50 mg/kg, sc) to induce PAH. Three weeks later, the rats were intravenously injected with MSCs, MSC-MVs or saline for 2 weeks. At the end of treatments, the hemodynamic parameters and pathological right ventricular and pulmonary arterial remodeling were analyzed in each group.
Results: The MSC-MVs showed general morphologic characteristics of MVs and expressed annexin V and CD29 markers under TEM, and their size ranged from 40 to 300 nm. Intravenous injection of MSC-MVs or MSCs significantly ameliorated the mean pulmonary artery pressure (mPAP) and mean right ventricle pressure (mRVP) in PAH rats. Furthermore, intravenous injection of MSC-MVs or MSCs significantly decreased the right ventricle (RV) hypertrophy and pulmonary arteriole area index (AI) and thickness index (TI) in PAH rats.
Conclusion: Intravenous injection of MSC-MVs or MSCs produces similar beneficial effects for treating PAH, and our results provide a basis for cell-free approach in stem cell therapy.
Keywords: stem cell therapy; bone marrow mesenchymal stem cell; microvesicle; pulmonary artery hypertension; chronic heart disease
This work was supported by the National Heart, Lung, and Blood Institute (HL-098637 to Yan-fang CHEN), National Natural Science Foundation of China (81370242 and 81270195), Guangdong Natural Science Foundation (S2013010015005), Science and Technology Planning Project of Guangdong Province (2012B031800224 and 2011B031800249), and Science and Technology Innovation Fund of Guangdong Medical College (STIF201128).
# These authors contributed equally to this work.
* To whom correspondence should be addressed.
E-mail yanfang.chen@wright.edu (Yan-fang CHEN); jychen271@126.com (Jian-ying CHEN)
Received 2014-01-02 Accepted 2014-05-26