Abstract 354: Host Immune Factors and Donor Adult Stem Cells Mediate Myocardial Ischemia Repair
Cellular therapy with non-hematopoietic adult stem cells (ASC) has emerged as a novel strategy for treatment of myocardial infarction (MI). Cells from non-identical donors, however, are typically rejected by the immune system of recipient. To overcome this barrier to transplantation we induced MI by left coronary artery ligation followed by direct intramyocardial injection of ASC or saline in cohorts of syngeneic C57BL/6 (B6) immune competent versus B6 Rag/IL2Rγc (Rag/γc) T-, B- and natural killer-cell immune deficient mice. We made an unexpected observation that heart function was significantly improved in ASC-treated B6 mice, but not in ASC-treated Rag/γc mice; and that the beneficial effect of ASC was inversely correlated with ASC persistence (i.e., ACS were rejected by B6 mice but engrafted in Rag/γc mice). As the donor cells were rejected within several weeks by B6 animals we hypothesized that the host immune system and ASC provided trophic signals for cardiac repair early after injury. In search for anatomical correlation, we first assessed changes in capillary density. Four weeks after MI, significantly more capillaries (normalized to number of nuclei) were observed in the border zone of B6 animals treated with ASC versus saline (p = 0.01), and significantly fewer capillaries were found in the infarct zone when B6 animals (treated with ASC) were depleted of T-cells and NK-cells (p = 0.03). To gain mechanistic insight into the early events in the ASC-mediated repair, next we have assessed one week after MI ± ASC messenger RNA expression of genes known to be engaged in angiogenesis. In B6 mice the most prominent change in response to MI injury was 17-fold increased expression of tissue inhibitor of metalloproteinases 1. The ASC mediated response to MI injury was defined by increased expression of fibroblast growth factor 2, integrin αV, phophorylated form of vascular endothelial growth factor receptor 2 and endothelial-specific receptor tyrosine kinase (all p < 0.01). These data are the first to define the paracrine tissue repair factors necessary to produce therapeutic benefit in response to donor ASC after MI. Importantly, our data also suggest that MI is not solely a heart lesion, but rather a systemic inflammatory condition controlled by host immune system.
This research has received full or partial funding support from the American Heart Association, AHA National Center.