Interleukin-10 From Transplanted Bone Marrow Mononuclear Cells Contributes to Cardiac Protection After Myocardial Infarction

Abstract

Abstract-Bone marrow mononuclear cells (BM-MNCs) have successfully been used as a therapy for the improvement of left ventricular (LV) function after myocardial infarction (MI). It has been suggested that paracrine factors from BM-MNCs may be a key mechanism mediating cardiac protection. We previously performed microarray analysis and found that the pleiotropic cytokine interleukin (IL)-10 was highly upregulated in human progenitor cells in comparison with adult endothelial cells and CD14 ϩ cells. Moreover, BM-MNCs secrete significant amounts of IL-10, and IL-10 could be detected from progenitor cells transplanted in infarcted mouse hearts. Specifically, intramyocardial injection of wild-type BM-MNCs led to a significant decrease in LV end-diastolic pressure (LVEDP) and LV end-systolic volume (LVESV) compared to hearts injected with either diluent or IL-10 knock-out BM-MNCs. Furthermore, intramyocardial injection of wild-type BM-MNCs led to a significant increase in stroke volume (SV) and rate of the development of pressure over time (ϩdP/dt) compared to hearts injected with either diluent or IL-10 knock-out BM-MNCs. The IL-10 -dependent improvement provided by transplanted cells was not caused by reduced infarct size, neutrophil infiltration, or capillary density, but rather was associated with decreased T lymphocyte accumulation, reactive hypertrophy, and myocardial collagen deposition. These results suggest that BM-MNCs mediate cardiac protection after myocardial infarction and this is, at least in part, dependent on IL-10. Key Words: acute myocardial infarction Ⅲ remodeling Ⅲ growth factors/cytokines Ⅲ cell therapy B one marrow-derived progenitor cells have been used clinically to improve left ventricular (LV) function in patients after acute myocardial infarction (MI), 1-4 however the exact mechanisms for this improvement in cardiac function have not clearly been defined. Several mechanisms have been proposed to explain the beneficial effects of this cell-based therapy including cell transdifferentiation, cell fusion, and the release of paracrine growth factors and cytokines. In support of the latter mechanism, various cytokines and growth factors from transplanted progenitor cells have been shown to be important in progenitor cell-mediated cardiac protection such as basic fibroblast growth factor, vascular endothelial growth factor, stromal-derived factor, 5,6 angiopoietin-1, interleukin (IL)-1␤, tumor necrosis factor-␣, 7,8 hepatocyte growth factor, insulin-like growth factor-1, thymosin ␤4, 8 secreted frizzled related protein 2, 9 IL-6, placental growth factor, transforming growth factor, monocyte chemoattractant protein-1, platelet-derived growth factor, plasminogen activator, and metalloproteinase-9. 10 We previously performed microarray analysis on peripheral blood-derived cultured human precursor cells 11 and found one paracrine factor highly expressed, the pleiotropic cytokine, IL-10. IL-10 is expressed and secreted by a variety of cell types such as T cells, monocytes/macrophages, dendritic cells, ...

Activation of Natural Killer T Cells Ameliorates Postinfarct Cardiac Remodeling and Failure in Mice

“…31 Moreover, the previous study by Burchfield et al showed that IL-10 from transplanted bone marrow mononuclear cells contributed to cardiac protection after MI in association with a decrease in T lymphocyte accumulation, reactive hypertrophy, and myocardial collagen deposition. 32 However, in the present study, zymographic MMP-9 level was not affected by αGC, which was consistent with the infiltration of lymphocyte observed by immunohistochemical staining for CD3 ( Figure 5). We also measured the protein levels of HuR/MMP-9 or STAT3 in the noninfarcted LV.…”

Effects of Experimental Asthma on Inflammation and Lung Mechanics in Sickle Cell Mice

“…Finally, the loss of antiinflammatory responses may also play a role in increasing pulmonary inflammation and airway hyperresponsiveness in SCD. For example, although IL-10, which decreases inflammation and prevents abnormal collagen deposition (24,25), was similar in Non-Sen chi-HbA and chi-SCD mice, after OVA-sensitization, OVASen chi-HbA mice were able to increase IL-10 production, but OVA-Sen chi-SCD mice were not. Failure to mount an antiinflammatory IL-10 response in the presence of robust increases in IL-5 and MCP-1 may account, at least in part, for the enhanced eosinophil recruitment and collagen deposition that occurred in the perialveolar and perivascular regions in the OVA-Sen chi-SCD mice.…”

The Therapeutic Potential of Stimulating Endogenous Stem Cell Mobilization

“…Delivery of BMSC to ischemic cardiac tissue has led to a significant increase in the concentration of IL-10, interleukin-1 (IL-1 ), tumor necrosis factor-(TNF-) and other cytokines in the cardiac tissue, which contributed to neovascularization and reduction of infarct size (Kamihata et al, 2001;Burchfield et al, 2008;Gnecchi et al, 2005;Mirotsou et al, 2011). Condition media in which BMSC were exposed to hypoxia proved to be cytoprotective to cardiomyocytes and was able to reduce infarct size (Gnecchi et al, 2006).…”