HucMSC-Exosome Mediated-Wnt4 Signaling Is Required for Cutaneous Wound Healing
HucMSC-Exosome Mediated-Wnt4 Signaling Is Required for Cutaneous Wound Healing
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DOI：
10.1002/stem.1771
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发表时间：
2015-07-01
期刊：
影响因子：
5.2
通讯作者：
Xu, Wenrong
中科院分区：
文献类型：
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作者：
Zhang, Bin;Wang, Mei;Xu, Wenrong
间充质干细胞来源的外泌体（Mesenchymal stem cell-derived exosomes，MSC-Ex）在组织损伤修复中发挥重要作用，但MSC-Ex在皮肤损伤修复中的作用及其机制尚不清楚。在此，我们使用大鼠皮肤烧伤模型检查了人脐带MSC衍生的外泌体（hucMSC-Ex）在皮肤伤口愈合中的益处。我们发现hucMSC-Ex处理的伤口表现出显著加速的上皮再生，体内CK 19、PCNA、胶原I（与胶原III相比）的表达增加。HucMSC-Ex可促进热应激后皮肤细胞的增殖，抑制热应激后皮肤细胞的凋亡。我们还发现，Wnt 4包含在hucMSC-Ex中，并且hucMSC-Ex衍生的Wnt 4促进β-catenin核转位和活性以增强皮肤细胞的增殖和迁移，这可以被β-catenin抑制剂ICG 001逆转。体内研究证实，通过hucMSC-Ex激活Wnt/β-连环蛋白在伤口再上皮化和细胞增殖中起关键作用。此外，hucMSC-Ex中Wnt 4的敲低在体外废除了β-连环蛋白活化和皮肤细胞增殖和迁移。当干扰hucMSC-Ex中Wnt 4的表达时，体内治疗效果也受到抑制。此外，hucMSC-Ex激活AKT通路与大鼠皮肤烧伤模型中热应激诱导的细胞凋亡减少有关。总的来说，我们的研究结果表明，外泌体递送的Wnt 4为MSC在皮肤伤口愈合中的治疗策略提供了新的方面。干细胞2015;33：2158-2168
Mesenchymal stem cell-derived exosomes (MSC-Ex) play important roles in tissue injury repair, however, the roles of MSC-Ex in skin damage repair and its mechanisms are largely unknown. Herein, we examined the benefit of human umbilical cord MSC-derived exosome (hucMSC-Ex) in cutaneous wound healing using a rat skin burn model. We found that hucMSC-Ex-treated wounds exhibited significantly accelerated re-epithelialization, with increased expression of CK19, PCNA, collagen I (compared to collagen III) in vivo. HucMSC-Ex promoted proliferation and inhibited apoptosis of skin cells after heat-stress in vitro. We also discovered that Wnt4 was contained in hucMSC-Ex, and hucMSC-Ex-derived Wnt4 promoted -catenin nuclear translocation and activity to enhance proliferation and migration of skin cells, which could be reversed by -catenin inhibitor ICG001. In vivo studies confirmed that the activation of Wnt/-catenin by hucMSC-Ex played a key role in wound re-epithelialization and cell proliferation. Furthermore, knockdown of Wnt4 in hucMSC-Ex abrogated -catenin activation and skin cell proliferation and migration in vitro. The in vivo therapeutic effects were also inhibited when the expression of Wnt4 in hucMSC-Ex was interfered. In addition, the activation of AKT pathway by hucMSC-Ex was associated with the reduction of heat stress-induced apoptosis in rat skin burn model. Collectively, our findings indicate that exosome-delivered Wnt4 provides new aspects for the therapeutic strategy of MSCs in cutaneous wound healing. Stem Cells 2015;33:2158-2168