Bone Marrow-Derived Mesenchymal Stem Cells Promoted Cutaneous Wound Healing by Regulating Keratinocyte Migration via β2-Adrenergic Receptor Signaling
Bone Marrow-Derived Mesenchymal Stem Cells Promoted Cutaneous Wound Healing by Regulating Keratinocyte Migration via β2-Adrenergic Receptor Signaling
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DOI：
10.1021/acs.molpharmaceut.7b01138
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发表时间：
2018-07-01
影响因子：
4.9
通讯作者：
Fu, Xiaobing
中科院分区：
文献类型：
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作者：
Huo, Jiahui;Sun, Sujing;Fu, Xiaobing
间充质干细胞(MSCs)在皮肤创面愈合过程中发挥着重要作用，但其作用机制尚不清楚。一系列研究表明，迁移到创面床层的角质形成细胞依赖于类似上皮-间充质转化(EMT)的过程来启动重新上皮化。因此，我们研究了骨髓间充质干细胞(BMSCs)能否影响人表皮角质形成细胞(HEKs)和永生化的人角质形成细胞系HaCaT细胞的生物学行为和诱导其EMT样特性，并探讨了BMSC介导的表型变化的信号通路。通过使用β(2)-肾上腺素能受体(β(2)-AR)选择性拮抗剂ICI-118,551或β(2)-AR小干扰RNA(SiRNA)阻断E-钙粘素、α-SMA和Snail家族转录因子的表达，我们发现β(2)-AR信号参与了体外培养的人角质形成细胞EMT样改变的诱导。β(2)-AR信号也影响人角质形成细胞系的集体和个体细胞迁移，ICI-118,551可减弱这种影响。用骨髓间充质干细胞条件培养液(BMSC-CM)处理细胞，不仅概括了异丙肾上腺素(ISO)对细胞迁移的影响，而且还诱导了HEKS和HaCaT细胞中β(2)-AR和一系列与间充质表型相关的蛋白的表达。同样，ICI-118,551或β(2)-AR siRNAs阻断了β(2)-AR，逆转了表皮角质形成细胞系对BMSC-CM暴露的两种反应。这些结果在我们的活体研究中得到了进一步的验证，表明外源性MSCs的应用促进了皮肤创面的愈合，并通过激活β(2)-AR信号使创面周围的角质形成细胞具有更多的迁移表型。本研究结果揭示了MSCs在创面再上皮化过程中的生化机制，为MSCs在慢性创面治疗中的广泛应用提供了可靠的理论依据。
Mesenchymal stem cells (MSCs) play an important role in cutaneous wound healing; however, the functional mechanisms involved in the healing process are poorly understood. A series of studies indicate that keratinocytes that migrate into the wound bed rely on an epithelial-mesenchymal transition (EMT)-like process to initiate re-epithelialization. We therefore examined whether bone marrow-derived MSCs (BMSCs) could affect biological behavior and induce EMT-like characteristics in the human epidermal keratinocytes (HEKs) and in the immortalized human keratinocyte cell line HaCaT cells, and we investigated the signaling pathways of BMSC-mediated phenotypic changes. By assessing the expression of EMT-related markers including E-cadherin, alpha-SMA, and Snail family transcription factors by beta(2)-adrenergic receptor (beta(2)-AR) blockage using ICI-118,551, a beta(2)-AR selective antagonist, or beta(2)-AR small interfering RNA (siRNA), we showed an involvement of beta(2)-AR signaling in the induction of EMT -like alterations in human keratinocytes in vitro. beta(2)-AR signaling also affected collective and individual cell migration in human keratinocyte cell lines, which was attenuated by administration of ICI-118,551. Treating the cells with BMSC-conditioned media (BMSC-CM) not only recapitulated the effect of isoproterenol (ISO) on cell migration but also induced the expression of beta(2)-AR and a panel of proteins associated with mesenchymal phenotype in HEKs and HaCaT cells. Similarly, a blockade of the beta(2)-AR by either ICI-118,551 or beta(2)-AR siRNAs reversed both responses of the epidermal keratinocyte cell lines relative to BMSC-CM exposure. These results were further verified in our vivo findings and indicated that the exogenous application of MSCs promoted cutaneous wound healing and endowed the keratinocytes surrounding the wound area with an increased migratory phenotype through activation of beta(2)-AR signaling. Our findings suggest a biochemical mechanism underlying the function of MSCs in wound re-epithelization, which provides a reliable theoretical basis for the wide application of MSCs in the treatment of chronic wounds.