Abstract 571: Role of Host Tissues for Sustained Humoral Effects Following Progenitor Cell Transplantation into the Ischemic Heart
Background: Humoral or paracrine activities have emerged as an important mechanism mediating the therapeutic effects of cell therapy. However, the role of host tissues following cell transplantation has been largely ignored. Here, we systematically investigated the serial expression patterns, biological effects and sources of humoral factors after transplantation of endothelial progenitor cells (EPCs) in myocardial infarction (MI).
Methods and Results: Wild type (WT) mice received mouse bone marrow (BM)-derived EPCs, endothelial cells or PBS in the peri-infarct area following MI. In the EPC group, we observed a higher capillary density, a higher proliferation rate of intramyocardial cells, a lower apoptosis rate in the peri-infarct area, and reduced infarct size. Although transplanted cells faded away within 7 days, real-time RT-PCR and immunoblot revealed that EPC transplantation induced a significant and sustained increase in various factors (VEGF, bFGF, Ang-1, IGF-1, HGF and SDF-1) over 14 days, a critical window for infarct repair. To resolve this mismatch between cellular engraftment and upregulated cytokines, we investigated the source of cytokines. We transplanted human EPCs into nude mice and performed real-time RT-PCR with human- and mouse-specific probes designed to detect the source of upregulated factors. Whereas the initial upregulation of various cytokines within 3 days after cell transplantation was attributed to a combination of transplanted (human) and host (mouse) cells, the sustained upregulation over 14 days was attributed to host cells. To investigate the contribution of host BM-derived cells, we induced MI in WT mice reconstituted with GFP-BM, and injected WT-EPCs. EPC transplantation significantly increased circulating BM-derived EPCs and Lin−c-kit+Sca-1+ cells and augmented the incorporation of host BM-derived cells into the site of neovascularization.
Conclusions: We demonstrate that EPC transplantation in MI, by inducing sustained humoral effects originating from host cells, augments proliferation of host myocardial cells and recruits BM-derived cells to repair myocardial injury. These data indicate that host tissues play a crucial role in repairing myocardial injury following cell transplantation.