ABSTRACT
An intra-myocardial injection of a cardiogenic factor (cardiogenin) was reported to induce myocardial regeneration of exogenous mesenchymal stem cell (MSCs) origin. In this study, replacement of the dangerous intra-myocardial injection with a safe method and whether the endogenous MSCs contribute to the cardiogenin-mediated myocardial regeneration were investigated. Bone marrow transplantation with labeled MSCs was performed in rats, which were subsequently subject to a permanent ligation of left anterior descending coronary artery one week after the transplantation. The rats were then treated with the cardiogenin through oral administration for 2 weeks. We not only demonstrated the substantial therapeutic effects of cardiogenin on myocardial infarction through an oral administration, but also provided direct evidences that the bone marrow derived endogenous MSCs are the major cellular source of the regenerating myocardium. Preliminary mechanistic studies suggested that miR-9 and its target E-cadherin may be required for intercalated disc formation.
Subject(s)
Bone Marrow Transplantation/methods , Cell Differentiation/drug effects , Mesenchymal Stem Cells/drug effects , Myocardial Infarction/therapy , Myocytes, Cardiac/cytology , Saponins/pharmacology , Animals , Cadherins/genetics , Cadherins/metabolism , Cells, Cultured , Disease Models, Animal , Echocardiography , Gene Expression Regulation , Geum/chemistry , Male , Mesenchymal Stem Cells/cytology , Myocardial Infarction/pathology , Plant Extracts/chemistry , Rats , Rats, Sprague-Dawley , Regeneration/drug effects , Saponins/administration & dosage , Whole-Body IrradiationABSTRACT
OBJECTIVES: To isolate the cardiogenic fraction, which can enhance cardiogenic differentiation of bone marrow-derived mesenchymal stem cells (MSC) from Geum japonicum. The therapeutic effect of the isolated cardiogenic fraction was further tested in a rat myocardial infarction (MI) model. METHOD: Bioassay guided fractionation method was used for the isolation of the cardiogenic fraction, named as heart repair fraction (HRF). MI was induced by a permanent ligation of left anterior descending coronary artery. The rats exhibiting similarly decreased values of left ventricle ejection fraction (LVEF) and fraction shortening (LVFS) were used. The rats in test group (n = 10) were subject to HRF treatment (20 mg×kg(-1)×d(-1)) through gastric gavage daily for 4 weeks. Water alone (2 ml/d) was given through gastric gavage to rats in the control group (n = 10). The cardiac function was assessed by echocardiography at different time points. Masson trichrome staining was used for evaluation of the infarct size. Morphological and immunohistochemical studies were performed to investigate the HRF mediated myocardial regeneration. RESULTS: LVEF (66.2% ± 6.9%) and LVFS (46.8% ± 5.8%) were significantly increased two weeks post HRF treatment compared with the values (LVEF: 55.7% ± 6.0% and LVFS: 36.4% ± 5.2%) in control rats (all P < 0.01). The improved heart function was further restored 4 weeks post HRF treatment (P < 0.01). Furthermore, the treatment of acute MI with this HRF significantly reduced the infarct size (19.0% ± 6.1%) compared with that (31.1% ± 8.6%) in control rats (P < 0.01). Substantial regeneration of cardiomyocytes in infarcted region of the HRF treated heart was also observed that replaced a considerable part of the infarcted heart tissues resulting in remarkable reduction of the infarct size. CONCLUSION: The properties of this HRF isolated from Geum japonicum in stimulating substantial regeneration of myocardium in infarct region with consequently improved cardiac function appear to be new and represent a new approach for the treatment of MI.
