Enhanced cell survival and paracrine effects of mesenchymal stem cells overexpressing hepatocyte growth factor promote cardioprotection in myocardial infarction

被引：87
作者：
Zhao, Liyan [1 ]
Liu, Xiaolin [1 ]
Zhang, Yuelin [2 ]
Liang, Xiaoting [3 ]
Ding, Yue [3 ]
Xu, Yan [1 ]
Fang, Zhen [1 ]
Zhang, Fengxiang [1 ]
机构：
[1] Nanjing Med Univ, Affiliated Hosp 1, Div Cardiol, Sect Pacing & Electrophysiol, Nanjing, Jiangsu, Peoples R China
[2] Univ Hong Kong, Li Ka Shing Fac Med, Dept Med, Div Cardiol, Hong Kong, Hong Kong, Peoples R China
[3] Tongji Univ, Shanghai East Hosp, Sch Med, Pudong Dist Clin Translat Med Res Ctr, Shanghai 200092, Peoples R China
来源：
EXPERIMENTAL CELL RESEARCH | 2016年 / 344卷 / 01期
基金：
中国国家自然科学基金;
关键词：
Mesenchymal stem cells; Hepatocyte growth factor; Myocardial infarction; Cytokines; ENDOTHELIAL-CELLS; PROLIFERATION; HEART; PATHOPHYSIOLOGY; CARDIOMYOCYTES; ENGRAFTMENT; ACTIVATION; THERAPY; HGF;
D O I：
10.1016/j.yexcr.2016.03.024
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
Poor cell survival post transplantation compromises the therapeutic benefits of mesenchymal stem cells (MSCs) in myocardial infarction (MI). Hepatocyte growth factor (HGF) is an important cytokine for angiogenesis, anti-inflammation and anti-apoptosis. This study aimed to evaluate the cardioprotective effects of MSCs overexpressing HGF in a mouse model of MI. The apoptosis of umbilical cord-derived MSCs (UC-MSCs) and HGF-UC-MSCs under normoxic and hypoxic conditions was detected. The conditioned medium (CdM) of UC-MSCs and HGF-UC-MSCs under a hypoxic condition was harvested and its protective effect on neonatal cardiomyocytes (NCMs) exposed to a hypoxic challenge was examined. UC-MSCs and HGF-UC-MSCs were transplanted into the peri-infarct region in mice following MI and heart function assessed 4 weeks post transplantation. The apoptosis of HGF-UC-MSCs under hypoxic conditions was markedly decreased compared with that of UC-MSCs. NCMs treated with HGF-UC-MSC hypoxic CdM (HGF-UC-MSCs-hy-CdM) exhibited less cell apoptosis in response to hypoxic challenge than those treated with UC-MSC hypoxic CdM (UC-MSCs-hy-CdM). HGF-UC-MSCs-hy-CdM released the inhibited p-ARt and lowered the enhanced ratio of Bax/Bcl-2 induced by hypoxia in the NCMs. HGF-UC-MSCs-hy-CdM expressed higher levels of HGF, EGF, bFGF and VEGF than UC-MSCs-hy-CdM. Transplantation of HGF-UC-MSCs or UC-MSCs greatly improved heart function in the mouse model of MI. Compared with UC-MSCs, transplantation of HGF-UC-MSCs was associated with less cardiomyocyte apoptosis, enhanced angiogenesis and increased proliferation of cardiomyocytes. This study may provide a novel therapeutic strategy for MSC-based therapy in cardiovascular disease. (C) 2016 Elsevier Inc. All rights reserved.
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页码：30 / 39
页数：10
相关论文
共 39 条
[21]   Myocardial protection from ischemia/reperfusion injury by endogenous and exogenous HGF [J].
Nakamura, T ;
Mizuno, S ;
Matsumoto, K ;
Sawa, Y ;
Matsuda, H ;
Nakamura, T .
JOURNAL OF CLINICAL INVESTIGATION, 2000, 106 (12) :1511-1519
[22]   Mesenchymal stem cells and their potential as cardiac therapeutics [J].
Pittenger, MF ;
Martin, BJ .
CIRCULATION RESEARCH, 2004, 95 (01) :9-20
[23]   Enhanced engraftment and repairing ability of human adipose-derived stem cells, conveyed by pharmacologically active microcarriers continuously releasing HGF and IGF-1, in healing myocardial infarction in rats [J].
Savi, Monia ;
Bocchi, Leonardo ;
Fiumana, Emanuela ;
Karam, Jean-Pierre ;
Frati, Caterina ;
Bonafe, Francesca ;
Cavalli, Stefano ;
Morselli, Paolo G. ;
Guarnieri, Carlo ;
Caldarera, Claudio M. ;
Muscari, Claudio ;
Montero-Menei, Claudia N. ;
Stilli, Donatella ;
Quaini, Federico ;
Musso, Ezio .
JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A, 2015, 103 (09) :3012-3025
[24]   Mesenchymal Stem Cells Pretreated with HGF and FGF4 Can Reduce Liver Fibrosis in Mice [J].
Shams, Sulaiman ;
Mohsin, Sadia ;
Nasir, Ghazanfar Ali ;
Khan, Mohsin ;
Khan, Shaheen N. .
STEM CELLS INTERNATIONAL, 2015, 2015
[25]   Mesenchymal Stem Cells Overexpressing Hepatocyte Growth Factor (HGF) Inhibit Collagen Deposit and Improve Bladder Function in Rat Model of Bladder Outlet Obstruction [J].
Song, Yun Seob ;
Lee, Hong Jun ;
Doo, Seung Hwan ;
Lee, Sun Ju ;
Lim, Inja ;
Chang, Kyu-Tae ;
Kim, Seung U. .
CELL TRANSPLANTATION, 2012, 21 (08) :1641-1650
[26]   Thioredoxin-1 (Trx1) engineered mesenchymal stem cell therapy increased pro-angiogenic factors, reduced fibrosis and improved heart function in the infarcted rat myocardium [J].
Suresh, Sumanth C. ;
Selvaraju, Vaithinathan ;
Thirunavukkarasu, Mahesh ;
Goldman, Joshua W. ;
Husain, Aaftab ;
Palesty, J. Alexander ;
Sanchez, Juan A. ;
McFadden, David W. ;
Maulik, Nilanjana .
INTERNATIONAL JOURNAL OF CARDIOLOGY, 2015, 201 :517-528
[27]   Left ventricular remodeling after myocardial infarction - Pathophysiology and therapy [J].
Sutton, MGS ;
Sharpe, N .
CIRCULATION, 2000, 101 (25) :2981-2988
[28]   Autologous Mesenchymal Stem Cells Mobilize cKit+ and CD133+ Bone Marrow Progenitor Cells and Improve Regional Function in Hibernating Myocardium [J].
Suzuki, Gen ;
Iyer, Vijay ;
Lee, Te-Chung ;
Canty, John M., Jr. .
CIRCULATION RESEARCH, 2011, 109 (09) :1044-1054
[29]  
Takagawa J., 1985, J APPL PHYSIOL, V102, P2104
[30]   Blockade of the Ras/MEK/ERK and Ras/PI3K/Akt pathways by statins reduces the expression of bFGF, HGF, and TGF-β as angiogenic factors in mouse osteosarcoma [J].
Tsubaki, Masanobu ;
Yamazoe, Yuzuru ;
Yanae, Masashi ;
Satou, Takao ;
Itoh, Tatsuki ;
Kaneko, Junichi ;
Kidera, Yasuhiro ;
Moriyama, Kenzo ;
Nishida, Shozo .
CYTOKINE, 2011, 54 (01) :100-107
1234