title: C-Kit Positive Cardiac Stem Cells and Bone Marrow-Derived Mesenchymal Stem Cells Synergistically Enhance Angiogenesis and Improve Cardiac Function After Myocardial Infarction in a Paracrine Manner.
abstract: BACKGROUND
  Stem cell transplantation offers a promising treatment for heart failure. Recent studies show that both c-kit positive cardiac stem cells (CSCs) and bone marrow-derived mesenchymal stem cells (BM-MSCs) are good candidates for stem cell therapy to treat heart failure; however, the exact mechanism of stem cell therapy in improving cardiac function of ischemic cardiomyopathy is not fully known. Our objective was to test our hypothesis that CSCs and/or BM-MSCs repair the damaged heart by boosting post-myocardial infarction (MI) angiogenesis in a paracrine manner.
  
  
  RESULTS
  We isolated and purified CSCs and BM-MSCs from rats. Intramyocardial injections of CSCs and/or BM-MSCs were performed at 28 days after MI. We applied cardiac ultrasound and histological analysis to evaluate the effect of cell therapy on cardiac function and cardiac remodeling. In vivo donor cell transplantation experiments showed that CSCs and/or BM-MSCs improved cardiac function after MI and reduced infarct size. However, in vivo cell tracking experiments showed that minimal donor cells remained in the myocardium after cell transplantation. Our further in vitro and in vivo experiments showed that transplantation of CSCs enhanced the expression of pro-angiogenic factors and boosted post-MI angiogenesis in the myocardium in a paracrine manner, which in part contributed to the effect of CSCs on cardiac recovery after MI. CSCs and BM-MSCs synergistically inhibited CSC/BM-MSC apoptosis and enhanced their proliferation in a paracrine manner. This resulted in a larger number of transplanted cells remaining in the post-MI myocardium after coinjection of CSCs and BM-MSCs, and therefore the accumulation of more pro-angiogenic factors in the heart tissue compared to transplantation of CSCs or MSCs alone. Consequently, transplantation of both CSCs and BM-MSCs was superior to transplantation of either CSCs or BM-MSCs alone to boost post-MI angiogenesis and improve cardiac function after MI.
  
  
  CONCLUSIONS
  C-kit+CSC and/or BM-MSC transplantation can improve cardiac function after MI in a paracrine manner. Coinjection of both CSCs and BM-MSCs improves cardiac function more significantly than CSC or BM-MSC transplantation alone in a paracrine manner by improving the engraftment of donor cells and boosting the expression of multiple pro-angiogenic factors.
authors.affiliation: Department of Cardiovascular Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Luer
authors.initials: L
authors.lastname: Bao
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Qingshu
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Shengqiong
authors.initials: S
authors.lastname: Deng
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Zuoren
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Cardiovascular Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Cardiovascular Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China. Electronic address: zhanglin1209@tongji.edu.cn.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Cardiovascular Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China. Electronic address: frankfan@tongji.edu.cn.
authors.forename: Huimin
authors.initials: H
authors.lastname: Fan
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000737:chemistry / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D007269:Injections, Intra-Arterial; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D019899:Paracrine Communication / Q000502:physiology*; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D019009:Proto-Oncogene Proteins c-kit
keywords: Myocardial infarction; angiogenesis; cardiac stem cells; heart failure; mesenchymal stem cells