Abstract 705: Adult Stem Cells and Host Immune Response Synergize to Stimulate Angiogenesis after Myocardial Ischemia
Bone marrow derived non-hematopoietic adult stem cells (ASC), termed Multipotent Adult Progenitor Cells, aid healing after myocardial infarction (MI). Remarkably however, host immune system was required for this beneficial effect. As heart function was directly correlated with capillary density and inversely correlated with ASC persistence, we hypothesized, that the host immune system and ASC provide trophic angiogenic signals for cardiac repair early after injury. Studies were performed using syngeneic C57BL/6 (B6) immune competent or B6 Rag/IL2Rγc (Rag/γc) T-, B- and natural killer-cell immune deficient recipients after left coronary artery ligation followed by direct intramyocardial injection of ASC or saline. To gain mechanistic insight into early events in the ASC-mediated repair, we have assessed cellular influx to the site of ischemia and myocardial expression of 84 genes involved in murine angiogenesis five days after MI and ASC infusion. Significantly more neutrophils and monocytes migrated into the site of MI in B6 mice given ASC when compared to non-ASC MI controls and to Rag/γc mice with MI given ASC. Consistent with this, angiogenic cytokines elaborated by neutrophils and monocytes (CCL-2, CCL-11, CXCL-1 and interleukin 1β) were significantly elevated when ASC were present in the B6 (but not in Rag/γc) infarcted hearts. As the productive tissue repair required both immune competency and paracrine effects of ASC, we focused next on statistically significant differences in angiogenic factors expressed in B6 versus Rag/γc both of which have undergone MI and ASC injections. Surprisingly, statistically significant changes in only seven differentially expressed factors characterized the angiogenic and myocyte sparing process: cytokine interferon γ, endothelial-specific receptor tyrosine kinase, platelet derived growth factor α, transforming growth factors β1 and β2, transcription factor Ephrin β2, and matrix protein serine/cysteine proteinase inhibitor 1. These data are the first to define the immune and paracrine tissue repair factors necessary to produce therapeutic benefit in response to donor adult stem cells after acute myocardial ischemic injury.