Abstract 13909: Contrast Ultrasound Molecular Imaging of the Pro-angiogenic Paracrine Effects of Stem Cell Therapy in Limb Ischemia
Background: Stem cell therapy is a promising treatment for chronic ischemic disease that may, in part, promote vascular remodeling through paracrine effects on endogenous cells. We used contrast-enhanced ultrasound (CEU) molecular imaging to test the hypothesis that stem cells recruit a pro-angiogenic subset of monocytic inflammatory cells through the expression of endothelial adhesion molecules that mediate monocyte rolling and adhesion.
Methods: Hind-limb ischemia was produced in wild-type mice by iliac ligation. One day later, either multipotential adult progenitor cells (MAPC) or saline vehicle was injected in the proximal hindlimb adductor muscles. On Day 3 and 21, CEU perfusion imaging and molecular imaging of vascular cell adhesion molecule-1 (VCAM-1), fractalkine (CX3CL-1), and the fractalkine receptor (CX3CR-1, a marker of pro-angiogenic monocytes) was performed. Intravital microscopy of ischemic cremaster muscle with and without MAPC therapy was used to evaluate leukocyte adhesion.
Results: Perfusion in ischemic muscle was higher (p<0.05) in the MAPC-treated than control mice at day 3 (0.41±0.26 vs 0.12±0.07 ml/min/g) and day 21 (0.53±0.12 vs 0.29±0.15 ml/min/g). Histology at day 3 detected a greater number of monocytes and, in particular, CX3CR-1-positive cells. On day 3 molecular imaging, MAPC treated muscle had greater VCAM-1 (13±4 vs 4±1, p=0.04) and CX3CR-1 (16±4 vs 3±1, p=0.02) signal, but not fractalkine (8±2 vs 4±2, p=0.17). At day 21, MAPC treated limbs showed only a trend toward higher signal for both CX3CR1 (7±2 vs 3±1, p=0.06) and for VCAM-1(5±2 vs 3±1, p=0.3). Intravital microscopy of ischemic muscle demonstrated migration of MAPCs to a peri-microvascular location within 2 days after their injection. Compared to controls, MAPC-treated muscles were characterized by slower rolling and greater adhesion of leukocytes in post-capillary venules.
Conclusions: In limb ischemia, MAPCs promote an early pro-angiogenic monocyte recruitment response through enhanced expression of leukocyte adhesion molecules that participate in leukocyte rolling and adhesion. This paracrine effect of MAPCs appears to have specificity for certain adhesion molecules and is likely important in their ability to promote vascular remodeling.
- © 2013 by American Heart Association, Inc.