Microvesicles from human adipose stem cells promote wound healing by optimizing cellular functions via AKT and ERK signaling pathways
Microvesicles from human adipose stem cells promote wound healing by optimizing cellular functions via AKT and ERK signaling pathways
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来自人类脂肪干细胞的微泡通过 AKT 和 ERK 信号通路优化细胞功能，促进伤口愈合
DOI：
10.1186/s13287-019-1152-x
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发表时间：
2019-01-31
影响因子：
7.5
通讯作者：
Chen, Zhenbing
中科院分区：
文献类型：
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作者：
Ren, Sen;Chen, Jing;Chen, Zhenbing
人脂肪干细胞（ASCs）已成为一种有前途的皮肤伤口治疗模式。最近的研究表明，干细胞的治疗作用部分由细胞外囊泡介导，细胞外囊泡包括外泌体和微囊泡。在这项研究中，我们研究了从ASC中分离的微泡的再生作用，并评估了ASC微泡促进伤口愈合的机制。方法采用差别化超离心分离细胞源性微囊泡（asc - mv）， PKH26染色，电镜和动态光散射（DLS）对其进行表征。我们在体外和体内研究了ASC-MV对角质形成细胞、成纤维细胞和内皮细胞的增殖、迁移和血管生成的影响。接下来，我们通过基因表达分析和AKT和ERK信号通路的激活水平来探讨ASC-MV刺激后三种细胞的潜在机制。然后，我们在体内皮肤损伤模型中评估了asc - mv对胶原沉积、新血管形成和再上皮化的影响。结果asc - mvs可被人脐静脉内皮细胞（HUVECs）、HaCAT和成纤维细胞内化，并在体外和体内显著促进这些细胞的增殖、迁移和血管生成。ASC-MV处理后，增殖标志物（cyclin D1、cyclin D2、cyclin A1、cyclin A2）和生长因子（VEGFA、PDGFA、EGF、FGF2）的基因表达显著上调。重要的是，asc - mv刺激了这些细胞中AKT和ERK信号通路的激活。创面局部注射asc - mv可显著增加创面的再上皮化、胶原沉积和新生血管形成，加速创面愈合。结论ASC-MVs可刺激HUVEC、HaCAT和成纤维细胞功能。ASC-MV治疗可显著加速伤口愈合，ASC-MV的益处可能与AKT和ERK信号通路有关。这说明了ASC-MVs的治疗潜力，它可能成为皮肤伤口愈合的一种新的治疗模式。
BackgroundHuman adipose stem cells (ASCs) have emerged as a promising treatment paradigm for skin wounds. Recent works demonstrate that the therapeutic effect of stem cells is partially mediated by extracellular vesicles, which comprise exosomes and microvesicles. In this study, we investigate the regenerative effects of isolated microvesicles from ASCs and evaluate the mechanisms how ASC microvesicles promote wound healing.MethodsAdipose stem cell-derived microvesicles (ASC-MVs) were isolated by differential ultracentrifugation, stained by PKH26, and characterized by electron microscopy and dynamic light scattering (DLS). We examined ASC-MV effects on proliferation, migration, and angiogenesis of keratinocytes, fibroblasts, and endothelial cells both in vitro and in vivo. Next, we explored the underlying mechanisms by gene expression analysis and the activation levels of AKT and ERK signaling pathways in all three kinds of cells after ASC-MV stimulation. We then assessed the effect of ASC-MVs on collagen deposition, neovascularization, and re-epithelialization in an in vivo skin injury model.ResultsASC-MVs could be readily internalized by human umbilical vein endothelial cells (HUVECs), HaCAT, and fibroblasts and significantly promoted the proliferation, migration, and angiogenesis of these cells both in vitro and in vivo. The gene expression of proliferative markers (cyclin D1, cyclin D2, cyclin A1, cyclin A2) and growth factors (VEGFA, PDGFA, EGF, FGF2) was significantly upregulated after ASC-MV treatment. Importantly, ASC-MVs stimulated the activation of AKT and ERK signaling pathways in those cells. The local injection of ASC-MVs at wound sites significantly increased the re-epithelialization, collagen deposition, and neovascularization and led to accelerated wound closure.ConclusionsOur data suggest that ASC-MVs can stimulate HUVEC, HaCAT, and fibroblast functions. ASC-MV therapy significantly accelerates wound healing, and the benefits of ASC-MVs may due to the involvement of AKT and ERK signaling pathways. This illustrates the therapeutic potential of ASC-MVs which may become a novel treatment paradigm for cutaneous wound healing.