Abstract 3419: Subacute Timing of Human CD34+ Cell Transplantation following Acute Myocardial Infarction Increases the Therapeutic Efficacy
Background: Clinical trials of autologous stem/progenitor cell therapy for myocardial infarction (MI) are ongoing. However, little is known about the efficacy of the therapy depending on the timing of cell transplantation after MI. We hypothesized that timing of cell transplantation might be critical to determine the therapeutic outcome in acute MI.
Methods and Results: Human CD34+ cells (5×105/rat) or PBS (control) were injected to nude rats (IV, n=8/each group) immediately (D0 & control), 3 days (D3), 5 days (D5) and 7 days (D7) after MI. UCG, hemodynamic and histological analyses were performed 6 weeks after MI. The D3 group exhibited the best-preserved LV function with reduced fibrosis and increased vascularity in peri-infarct zone among the all groups. Overall, the extent of cardiac function was as follows: D3 > = D5 > D7 = D0 > control. Next, we examined acute and late recruitment of the injected DiI labeled CD34+ cells to ischemic myocardium one day and 14 days after the treatment by immunostaining. Although there was no significant difference of CD34+ cell number at day 14 among the all groups, the acutely recruited CD34+ cell number was striking in the D3 group compared with the other groups (D3 > D5 > D7 >> D0) consistent with cardiac functions. In addition, the D3 group exhibited frequent CD34+ cell participation in the neovasculature. To identify specific genes that can affect CD34+ cell recruitment, we further comprehensively examined 96 rat cardiac gene expressions by real-time RT-PCR after MI at the above timing, and detected the peak expressions of SDF-1α/β, PLGF, MMP-14 and IGF-1 at day 3, and IL-1β and TNFα at day 0 (16 h), suggesting that key factors for stem/progenitors expressed in subacute phase (D3/D5) while cytotoxic factors did in acute phase (16 h) in ischemic myocardium after MI. These gene expressions might explain the striking recruitment of CD34+ cells and the best outcome in the D3 group.
Conclusion: Subacute (D3) timing of systemic CD34+ cell infusion exhibited the best cardiac functional recovery due to the striking cell recruitment, perhaps, with the paracrine effect for myocardial preservation. Our data suggest that the timing of cell transplantation may be a critical factor to increase the efficacy of autologous cell therapy for MI.