Abstract 9926: Molecular Imaging of the Pro-angiogenic Paracrine Effects of Stem Cell Therapy

Abstract

Background: Pro-angiogenic stem cells are a promising therapy for patients with severe coronary or peripheral vascular disease. Mechanisms by which cell therapy promotes vascular remodeling remain unclear. We applied contrast-enhanced ultrasound (CEU) molecular imaging to test whether cell therapy acts in a paracrine fashion by promoting recruitment of pro-angiogenic (CX3CR-1 hi ) monocytes. Methods: Unilateral hindlimb ischemia was produced in 52 mice by iliac artery ligation. One day later, the proximal hindlimb received either: (1) IM injection of 1×10 6 multipotent adult progenitor cells (MAPC), (2) sham saline injection, or (3) no therapy. At Day3, 7, and 21 CEU perfusion imaging and molecular imaging of CX3CR-1 and P-selectin were performed. In 8 separate mice, intravital microscopy of TNF-a-treated cremaster muscle was performed 3 days after injection of either 5×10 5 MAPCs or saline. Results: Arterial ligation resulted in a 70% reduction in limb muscle blood flow to 0.20±0.06 ml/min/g. MAPC therapy produced a more rapid and complete recovery of flow (0.61±0.06 ml/min/g at day 21, ≈25% higher than both control groups, p<0.05). Signal for CX3CR-1 was significantly (p<0.05) higher vs control groups at all 3 study intervals (Figure),corroborated by a marked increase in tissue monocytes on Mac-2 immunohistology. P-selectin signal was also significantly higher in the MAPC-treated mice at days 3 and 7 (Figure). Intravital microscopy which showed that MAPCs migrated to a perivascular location and produced a 50% increase in leukocyte rolling flux fraction. Conclusions: In chronic limb ischemia, MAPCs migrate to a perivascular location and promote the sustained recruitment of pro-angiogenic monocytes, in part through effects on endothelial adhesion molecule expression. These results suggest that cell therapy can act to promote vascular remodeling through inflammatory pathways