PTH Derivative Promotes Chronic Wound Healing via Synergistic Multicellular Stimulating and Exosomal Activities

Abstract

Background: Chronic diabetic wounds are a disturbing and rapidly growing clinical problem. Parathyroid hormone related peptide (PTHrP-2) was assumed as multifunctional factor in angiogenesis, fibrogenesis and re-epithelization. This study aims to test PTHrP-2 efficiency and mechanism in chronic wound healing. Methods: Through repair phenomenon in vivo some problems were detected, and further research on their mechanisms was made. In vivo therapeutic effects of PTHrP-2 was determined by HE, Masson, microfil and immunohistochemical staining. In vitro direct effects of PTHrP-2 was determined by proliferation, migration, Vascular Endothelial Grown Factor and collagen I secretion of cells and Akt/ Erk1/2 pathway change. In vitro indirect effects of PTHrP-2 was study via exosomes. Exosomes from PTHrP-2 untreated and treated HUVECs and HFF-1 cells were insolated and identified. Exosomes were co-cultured with original cells, HUVECs or HFF-1 cells, and epithelial cells. Proliferation and migration and pathway change were observed. PTHrP-2-HUVEC-Exos was added into in vivo wound to testify its hub role in PTHrP-2 indirect effects in wound healing. Results: In vivo, PTHrP-2 exerted multifunctional pro-angiogenesis, pro-firbogenesis and re-epithelization effects. In vitro, PTHrP-2 promoted proliferation and migration of endothelial and fibroblast cells, but had no effect on epithelial cells. Therefore, we tested PTHrP-2 indirect effects via exosomes. PTHrP-2 intensified intercellular communication between endothelial cells and fibroblasts and initiated endothelial-epithelial intercellular communication. PTHrP-2-HUVEC-Exos played hub role in PTHrP-2 indirect effects in wound healing. Conclusion: The findings of this study indicate that PTHrP-2, a multifunctional factor, can promote chronic wound healing via synergistic multicellular stimulating and exosomal activities.