Abstract 15686: Inflammatory Cytokine Secretion by Human Mesenchymal Stromal Cells is a Major Determinant of Cardiac Remodeling after Cell Therapy
Background: The cellular mechanisms associated with improved LV function after cell therapy remain unclear. We aimed to explore the differences in reparative properties among human mesenchymal stromal cells (hMSCs) from different sources and to determine the correlation between cytokine profiles and infarct repair in rat.
Methods and Results: We isolated and grew hMSCs from 4 different sources: 1) epicardial fat, 2) subcutaneous (SC) fat, 3) the right atrium (RA) and 4) bone marrow (BM). We then evaluated cytokine secretion profiles, and found that the RA and epicardial fat MSCs secreted the highest amounts of trophic factors, such as basic fibroblast growth factor and hepatocyte growth factor (p<0.05), as well as inflammatory cytokines, such as TNF-α and tissue inhibitor of metalloproteinase-2 (TIMP-2) (p<0.05). Notably, SC fat hMSCs secreted the lowest levels of inflammatory cytokines (p<0.05). Consequently, conditioned medium from RA and epicardial fat hMSCs produced the greatest angiogenic effect by matrigel tube formation assay. Next, we allocated rats (n=57) to 6 treatment groups, 7 days after MI: 1) RA-hMSCs in matrigel, 2) epicardial fat hMSCs in matrigel, 3) SC-hMSCs in matrigel, 4) BM-hMSCs in matrigel, 5) matrigel and 6) saline. Indeed, after 1 month, RA-hMSCs induced the highest number of vessels in the infarct, and together with BM-hMSCs, the highest score of infarct inflammation. However, by 2D-echo, LV dilatation was greatest in RA-hMSC-treated rats, and lowest in SC-hMSCs. Notably, there was a close correlation between the means of hMSC TNF-α and TIMP-2 secretion, and LV dilatation, as measured by change in LV diastolic area, before and 1 month after cell therapy (Figure).
Conclusions: The origin of MSCs dictates their reparative and immuno-modulatory properties. Inflammatory cytokines secreted by hMSCs are a major determinant of LV dilatation, suggesting that regulation of inflammation is a key mechanism in cell therapy for infarct repair.
- © 2012 by American Heart Association, Inc.