Impact Of Escaped Bone Marrow Mesenchymal Stromal Cells On Extra-cardiac Organs After Intramvocardial Implantation In A Rat Myocardial Infarction Model

Objectives:Recent years have witnessed a growing interest and enthusiasm in the application of bone-marrow derived stromal cell-based therapies to repair or regenerate damaged myocardium. Intramyocardial injection has become the most effective route of cell infusion precisely to the target area. Cell escape would occur after intramyocardial injection for the treatment of myocardial infarction (MI) and then the migrated cells would be entrapped by the extra-cardiac organs especially by the filter organs of the systemic and pulmonary circulation. We investigated the distribution and fate of injected bone marrow-derived mesenchymal stromal cells (MSCs) and their impact on the lung, liver and spleen.Materials and Methods:MSCs were isolated from male donor Lewis rat. Myocardial infarction was induced by left anterior descending artery ligation in female Lewis rats. Three weeks later, the qualified female rats with left ventricular ejection fraction (LVEF) lower than 60% and left ventricular fractional shortening (LVFS) lower than 30% were randomly divided for 2 groups. In cell transplantation group,3 millions male MSCs or phosphate buffered solution was injected into infarcted myocardium.10 healthy rats received intramyocardial PBS injection and were served as sham group. Four weeks after cell transplantation, left ventricular function were evaluated.The blood was obtained for the assessment of liver function, routine blood test and the level of immunoglobulin M. Tumour necrosis factor-a (TNF-a) and interleukin-1β(IL-1β) level in lung were measured with antibody enzyme-linked immunosorbent assays (ELISA) with commercial ELISA kits. The myeloperoxidase (MPO) activity of lung tissue was measured in colorimetric method. The cell retention was evaluated by quantitative real time-polymerase chain reaction (qRT-PCR). Immunohistochemistry study was performed to identify the migrated cells and differentation.Results:Heart function was improved after cell injection. qRT-PCR results showed the number of retained cells in spleen, liver and lung ranked 2nd,3rd and 4th followed by the heart without any adverse effects after cell transplantation. Conversely, a significant elevation in serum ALB level and a significant decreasein ALT level in cell transplantation group. It shows partly improve the liver function. The implanted MSCs which escaped to the liver, spleen and lung did not differentiate into fibroblast, myofibroblast or alveolar epithelial cell. The expressing the markers of functional hepatocytes was observed in few escaped MSCs.Conclusions:Cell migration after intramyocardial injection didn't result in the deterioration of lung, liver and spleen function. However, the biosafety of other stem cells resource on extra-cardiac organs need further investigation.