Synergistic effect of sustained delivery of basic fibroblast growth factor and bone marrow mononuclear cell transplantation on angiogenesis in mouse ischemic limbs

Combined angiogenic therapies may be superior to single angiogenic therapy for treatment of limb ischemia. First, we investigated whether the angiogenic efficacy of basic fibroblast growth factor (bFGF) administration and bone marrow-derived mononuclear cell (BMMNC) transplantation can be enhanced by sustained delivery (SD) of bFGF and BMMNC transplantation using a matrix, respectively, in mouse ischemic limbs. Next, we investigated whether the angiogenic efficacy of combination of two angiogenic strategies is superior to either strategy alone. One day after surgical induction of mouse hindlimb ischemia, mice were randomized to receive either no treatment, daily injection (DI) of bFGF, SD of bFGF, BMMNC transplantation using culture medium, BMMNC transplantation using fibrin matrix (FM), or combination of SD of bFGF with BMMNC transplantation using FM. The SD of bFGF significantly increased the microvessel density, compared with DI of bFGF (659±48/mm2 versus 522±39/mm2, p<0.05p<0.05). BMMNC transplantation using FM significantly increased the microvessel density, compared with BMMNC transplantation using culture medium (523±103/mm2 versus 415±75/mm2, p<0.05p<0.05). Importantly, combination of bFGF sustained release with BMMNC transplantation using FM further increased the densities of microvessels and arterioles, compared to either strategy alone (p<0.05p<0.05). The SD method of angiogenic protein and cell transplantation using matrix potentiate the angiogenic efficacy of bFGF and BMMNC transplantation, respectively, for limb ischemia. In addition, the combined therapy of SD of bFGF and BMMNC transplantation synergistically enhances angiogenesis in mouse ischemic limb, compared to each separate therapy.