Abstract-In this study, we hypothesized that bone marrow stem cells (BMSCs) protect ischemic myocardium through paracrine effects that can be further augmented with preconditioning. In in vitro experiments, cell survival factors such as Akt and eNOS were significantly increased in BMSCs following anoxia. In the second series of experiments following coronary ligation in mice, left ventricles were randomly injected with the following: DMEM (G-1), BMSCs (G-2), and preconditioned BMSCs (G-3). Four days after myocardial infarction, BMSCs were observed within injured myocardium in G-2 and G-3. Apoptotic cardiomyocytes within periinfarct area were significantly reduced in G-3. Four weeks after myocardial infarction, smaller left ventricular (LV) dimension and increased LV ejection fraction were observed in G-3. Infarct area was significantly reduced in G-3. However, GFP ϩ cardiomyocytes were observed in low numbers within periinfarct area in G-2 and G-3. In conclusion, BMSCs secreted cell survival factors under ischemia, and they prevented apoptosis in cardiomyocytes adjacent to the infarcted area. Preconditioning of BMSCs enhanced their survival and ability to attenuate LV remodeling, which was attributable, in part, to paracrine effects. (Circ Res.
2006;98:1414-1421.)Key Words: stem cells Ⅲ paracrine effect Ⅲ preconditioning Ⅲ ischemia Ⅲ remodeling M yocardial infarction (MI) leads to cardiomyocyte loss and scar formation in the infarcted area. The large transmural infarction is associated with ventricular remodeling after MI. 1 Ventricular remodeling is characterized by changes in left ventricular (LV) geometry, mass, volume, and function, which include hypertrophy and cellular apoptosis of cardiomyocytes, in response to myocardial injury or alteration in load. 2 Ventricular remodeling is also a major factor in the progression of heart failure, and the prognosis for survival is poor.One approach proposed to reverse myocardial remodeling is regeneration of new cardiomyocytes. Recent reports have shown that bone marrow stem cells (BMSCs) have multilineage differentiation potential and potentially cross the lineage restriction to form various nonhematopoietic tissues including heart. 3 Most studies on BMSC therapy in experimental animal heart models 4 -6 and patients with acute MI 7-9 have shown an improvement in cardiac function, signifying the safety and feasibility of this approach. However, the mechanism of BMSC therapy is still controversial. BMSCs repair the ischemic myocardium primarily by angioblast-mediated vasculogenesis, 10,11 prevention of apoptosis of native cardiomyocytes, or direct regeneration of the lost cardiomyocytes.We, therefore, hypothesized that BMSCs protected ischemic myocardium through paracrine effects that could be further augmented with preconditioning.
Materials and MethodsAn expanded Materials and Methods section can be found in the online data supplement available at http://circres.ahajournals.org.
Coculture of BMSCs and CardiomyocytesIsolation and purification of BMSCs from C57B6 mice ...
