BACKGROUND Diabetic wounds are a disturbing and rapidly growing clinical problem. A novel peptide, parathyroid hormone related peptide (PTHrP-2), is assumed as multifunctional factor in angiogenesis, fibrogenesis and re-epithelization. This study aims to test PTHrP-2 efficiency and mechanism in 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 were determined by HE, Masson, microfil and immunohistochemical staining. In vitro direct effects of PTHrP-2 were 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 were 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 a hub role in PTHrP-2 indirect effects in wound healing. CONCLUSION These findings of this study indicated that PTHrP-2, a multifunctional factor, could promote wound healing via synergistic multicellular stimulating and exosomal activities.

中文翻译：

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PTH衍生物通过协同多细胞刺激和外泌体活动促进伤口愈合。

背景技术糖尿病伤口是令人困扰且迅速增长的临床问题。一种新型肽，甲状旁腺激素相关肽（PTHrP-2）被认为是血管生成，纤维生成和再上皮形成的多功能因子。这项研究旨在测试PTHrP-2在伤口愈合中的效率和机制。方法通过体内修复现象发现一些问题，并对其机理进行进一步研究。通过HE，Masson，microfil和免疫组织化学染色确定PTHrP-2的体内治疗效果。PTHrP-2的体外直接作用由细胞增殖，迁移，血管内皮生长因子和胶原蛋白I分泌以及Akt / Erk1 / 2途径变化来确定。通过外泌体研究了PTHrP-2的体外间接作用。分离并鉴定了来自未经处理的和未处理的HUVEC和HFF-1细胞的PTHrP-2的外来体。外泌体与原始细胞，HUVEC或HFF-1细胞以及上皮细胞共培养。观察到增殖和迁移以及途径改变。将PTHrP-2-HUVEC-Exos添加到体内伤口中，以证明其在伤口愈合中PTHrP-2间接作用中的枢纽作用。结果在体内，PTHrP-2发挥了多功能的促血管生成，促成纤维和再上皮作用。在体外，PTHrP-2促进内皮细胞和成纤维细胞的增殖和迁移，但对上皮细胞没有影响。因此，我们通过外泌体测试了PTHrP-2的间接作用。PTHrP-2增强了内皮细胞与成纤维细胞之间的细胞间通讯，并启动了内皮-上皮细胞间通讯。PTHrP-2-HUVEC-Exos在伤口愈合中的PTHrP-2间接作用中起了枢纽作用。结论这项研究的这些发现表明PTHrP-2是一种多功能因子，可以通过协同的多细胞刺激和外泌体活性促进伤口愈合。