Priming with proangiogenic growth factors and endothelial progenitor cells improves revascularization in linear diabetic wounds

Abstract

In the present study, we investigated whether proangiogenic growth factors and endothelial progenitor cells (EPCs) induce favourable effects on cutaneous incisional wound healing in diabetic mice. The proangiogenic effects of human EPCs were initially analyzed using a HUVEC in vitro angiogenesis assay and an in vivo Matrigel assay in nude mice (n=12). For the diabetic wound model, 48 Balb/c mice with streptozotocin (STZ)-induced diabetes were divided randomly into 4 groups (12 mice in each group). Subsequently, 3, 5 and 7 days before a 15-mm full-thickness incisional skin wound was set, group 1 was pre-treated subcutaneously with a mixture of vascular endothelial growth factor (VEGF)/basic fibroblast growth factor (bFGF)/platelet-derived growth factor (PDGF) (3.5 μg of each), group 2 with 3.5 μg PDGF and group 3 with an aliquot of two million EPCs, whereas the control animals (group 4) were pre-treated with 0.2 ml saline solution. The wounds were assessed daily and the repaired tissues were harvested 7 days after complete wound closure. The angiogenesis assay demonstrated significantly increased sprout densities, areas and lengths in the EPC-treated group (all p<0.01). In the Matrigel assay, significantly increased microvessel densities, areas and sizes (all p<0.001) were also detected in the EPC-treated group. In the STZ-induced model of diabetes, the animals pre-treated with a combination of proangiogenic factors and EPCs showed in general, a more rapid wound closure. Vessel densities were >2-fold higher in the mice treated with a combination of proangiogenic factors and EPCs (p<0.05) and tensile strengths were higher in the groups treated with proangiogenic growth factors compared to the controls (p<0.05). These results suggest a beneficial effect of pre-treatment with proangiogenic growth factors and EPCs in incisional wound healing.

Specific Role of Impaired Glucose Metabolism and Diabetes Mellitus in Endothelial Progenitor Cell Characteristics and Function

“…90 Pretreatment of EPCs with proangiogenic growth factors, including VEGF, basic fibroblast growth factor, and platelet-derived growth factor, improves incisional wound healing (as assessed by angiogenesis assay, Matrigel assay, and vessel densities) in diabetic mice. 91 Furthermore, in vitro treatment with ephrin-B2/Fc improves the adhesion and migration of peripheral blood mononuclear cells, raises the number of circulating vascular progenitor cells, and enhances their proangiogenic potential in the diabetic mouse model. 92 Moreover, folic acid treatment also shows to normalize the majority of the altered gene expression profiles of EPCs from patients with type 1 DM compared with healthy subjects.…”

Exosomes Derived from Human Endothelial Progenitor Cells Accelerate Cutaneous Wound Healing by Promoting Angiogenesis Through Erk1/2 Signaling

“…Accumulating studies showed that the transplantation of endothelial progenitor cells (EPCs) derived from human peripheral blood or umbilical cord blood (UCB) can stimulate new capillaries formation and wound closure in diabetic animal models 5, 6. EPCs are the precursors of endothelial cells and can differentiate into mature endothelial cells that directly contribute to angiogenesis and vascular regeneration 7.…”

Vascular precursor cells in tissue injury repair

“…These precursors actively produce vasculogenic mediators (such as VEGF, IL-8, and PDGF) and other growth factors [such as bFGF, keratinocyte growth factor (KGF)] to exert paracrine stimulation of vascularization and injury repair. Local proangiogenic priming by injecting a mixture of VEGF, bFGF, and PDGF prior to implantation of EPCs has been observed to further improve the effectiveness of neovascularization and wound healing in diabetic animals 265 . Enhancing growth of marrow-derived EPCs in PolyCaprolactone-Gelatin (PCG) nano-fiber matrix in culture and then applying this PCG-EPCs matrix to the wound of diabetic mice can achieve sustained delivery of EPCs onto the diabetic wounds and enhance fibrosis-free wound healing 266 .…”