Abstract
Previous work in our laboratory has described several pro-angiogenic short peptides derived from endothelial extracellular matrices degraded by bacterial collagenase. Here we tested whether these peptides could stimulate wound healing in vivo. Our experiments demonstrated that a peptide created as combination of fragments of tenascin X and fibrillin 1 (comb1) applied into cranial dermal wounds created in mice treated with cyclophosphamide to impair wound healing, can improve the rate of wound closure. Furthermore, we identify and characterize a novel peptide (UN3) created and modified from two naturally-occurring peptides, which are present in human platelet-rich plasma. In vitro testing of UN3 demonstrates that it causes a 50% increase in endothelial proliferation, 250% increase in angiogenic response and a tripling of epithelial cell migration in response to injury. Results of in vivo experiments where comb1 and UN3 peptides were added together to cranial wounds in cyclophosphamide-treated mice leads to improvement of wound vascularization as shown by an increase of the number of blood vessels present in the wound beds. Application of the peptides markedly promotes cellular responses to injury and essentially restores wound healing dynamics to those of normal, acute wounds in the absence of cyclophosphamide impairment. Our current work is aimed at understanding the mechanisms underlying the stimulatory effects of these peptides as well as identification of the cellular receptors mediating these effects.
Highlights
Despite significant progress that has been achieved in our understanding of normal wound healing process and the pathologies that lead to wound chronicity, chronic wounds of differing etiology remain a significant health care burden affecting over 5 million people annually in the United States, alone [1]
On platelets accumulate at the site of injury, and participate in blood clotting and inflammatory cascades releasing interleukin 1b (IL-1b) and IL-8 necessary for monocyte adhesion and neutrophil activation respectively [4,5,6], activated platelets release key cellular survival factors, such as platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and epidermal growth factor [7,8] which stimulate cellular migration, proliferation and angiogenesis necessary for successful wound healing
In our previous study we described and characterized in vitro effects of several pro-angiogenic peptides derived from endothelial ECM degraded by bacterial collagenase [10]
Summary
Despite significant progress that has been achieved in our understanding of normal wound healing process and the pathologies that lead to wound chronicity, chronic wounds of differing etiology remain a significant health care burden affecting over 5 million people annually in the United States, alone [1]. On platelets accumulate at the site of injury, and participate in blood clotting and inflammatory cascades releasing interleukin 1b (IL-1b) and IL-8 necessary for monocyte adhesion and neutrophil activation respectively [4,5,6], activated platelets release key cellular survival factors, such as platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and epidermal growth factor [7,8] which stimulate cellular migration, proliferation and angiogenesis necessary for successful wound healing. This work is aimed at characterization of small peptides derived from endothelial extracellular matrices and extracts of platelet rich human plasma that could be used as stimulators of cellular responses to injury. We test a hypothesis that to native platelet products, platelet-rich plasma derived peptides (PDP) would stimulate cellular proliferation, migration and morphogenesis. We demonstrate increased wound reepithelialization, granulation tissue formation and restoration of wound healing ability in animals whose healing responses had been compromised by cyclophosphamide treatment
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