Mesoglycan induces the secretion of microvesicles by keratinocytes able to activate human fibroblasts and endothelial cells: A novel mechanism in skin wound healing
Mesoglycan induces the secretion of microvesicles by keratinocytes able to activate human fibroblasts and endothelial cells: A novel mechanism in skin wound healing
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DOI：
10.1016/j.ejphar.2019.172894
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发表时间：
2020-02-15
影响因子：
5
通讯作者：
Petrella, Antonello
中科院分区：
文献类型：
--
作者：
Belvedere, Raffaella;Pessolano, Emanuela;Petrella, Antonello
中聚糖是一种纤维蛋白溶解化合物，但最近已经报道了在皮肤伤口修复中有希望的促愈合作用。以前，我们已经表明，中聚糖激活人角质形成细胞，成纤维细胞和内皮细胞，并诱导分泌的微泡（EV），特别是外来体，从角质形成细胞。这些EV可能有助于伤口愈合，因为它们进一步激活细胞产生具有正反馈的自分泌回路。在这项工作中，从角质形成细胞分离的EV，用中聚糖处理，已在人成纤维细胞和内皮细胞上进行了测试。通过伤口愈合/侵袭试验进行了体外研究，以分析细胞运动性并评估分化过程。然后，通过人内皮细胞形成毛细血管样结构来评估体外血管生成。我们发现，中聚糖处理的角质形成细胞分泌的EV促进成纤维细胞和内皮细胞的迁移和侵袭。此外，这些接受细胞获得间充质表型。此外，血管生成出现强烈增强存在这种EV。总之，我们表明，来自角质形成细胞的EV触发旁分泌正反馈，能够进一步放大中聚糖的作用。这一机制与先前报道的自分泌循环相结合，并以成纤维细胞和内皮细胞的活化而达到高潮。特别地，这种激活通过生长因子的作用而放大，如对于成纤维细胞的FGF-2（成纤维细胞生长因子-2）和对于内皮细胞的VEGF（血管内皮生长因子）。
Mesoglycan is a fibrinolytic compound but recently promising pro-healing effects in skin wound repair have been reported. Previously, we have showed that mesoglycan activates human keratinocytes, fibroblasts and endothelial cells and induces the secretion of microvesicles (EVs), particularly exosomes, from keratinocytes. These EVs may contribute to wound healing since they further activate cells generating an autocrine loop with a positive feedback.In this work, EVs isolated from keratinocytes, treated with mesoglycan, have been tested on human fibroblasts and endothelial cells. The in vitro investigation has been carried out through Wound-Healing/invasion assays to analyze cell motility and assess the differentiation process. Then, the formation of capillary-like structures by human endothelial cells has been performed to evaluate in vitro angiogenesis.We found that EVs secreted from keratinocytes treated with mesoglycan promote fibroblasts and endothelial cells migration and invasion. Furthermore, these receiving cells acquire a mesenchymal phenotype. Additionally, the angiogenesis appears strongly enhanced in presence of this kind of EVs.In conclusion, we show that EVs deriving from keratinocytes trigger a paracrine positive feedback able to further amplify the effects of mesoglycan. This mechanism adds up to the autocrine loop previously reported and culminates with the activation of fibroblasts and endothelial cells. Particularly, this activation is amplified by the action of growth factors as FGF-2 (Fibroblast Growth Factor-2) for the fibroblasts and by VEGF (Vascular Endothelial Growth Factor) for the endothelial cells.