Shock Wave Treatment Enhances Cell Proliferation and Improves Wound Healing by ATP Release-coupled Extracellular Signal-regulated Kinase (ERK) Activation
Shock Wave Treatment Enhances Cell Proliferation and Improves Wound Healing by ATP Release-coupled Extracellular Signal-regulated Kinase (ERK) Activation
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DOI：
10.1074/jbc.m114.580936
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发表时间：
2014-09-26
影响因子：
4.8
通讯作者：
Ruenzler, Dominik
中科院分区：
文献类型：
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作者：
Weihs, Anna M.;Fuchs, Christiane;Ruenzler, Dominik
在不同的临床情况下，冲击波治疗可以加速受损伤口的愈合。然而，冲击波有益效应的潜在机制尚未完全揭示。由于细胞增殖是创面愈合级联反应的主要要求，我们采用体外实验和体内创面愈合模型来研究冲击波处理是否通过改变参与细胞增殖的主要细胞外因子和信号通路来影响细胞增殖。我们发现，以能量和脉冲数依赖的方式释放的细胞外ATP是冲击波治疗生物效应的触发因素。冲击波处理可诱导三种不同细胞类型(C3H10T1/2小鼠间充质干细胞、原代人类脂肪组织来源干细胞和人JurkatT细胞系)在体外释放ATP，增加ERK1/2和p38MAPK活性，并促进其增殖。嘌呤能信号诱导的ERK1/2激活被发现是这种增殖效应的关键，这一点在大鼠创伤愈合模型的体内研究中进一步得到证实，在该模型中，冲击波处理以ERK1/2依赖的方式诱导增殖并促进伤口愈合。综上所述，本报告证明了冲击波处理可触发细胞内ATP的释放，随后激活嘌呤能受体，最终通过ERK1/2下游信号促进体外和体内的增殖。总之，我们的发现进一步阐明了冲击波治疗发挥其有益作用的分子机制。这些发现有助于提高冲击波治疗创面愈合的临床应用。
Shock wave treatment accelerates impaired wound healing in diverse clinical situations. However, the mechanisms underlying the beneficial effects of shock waves have not yet been fully revealed. Because cell proliferation is a major requirement in the wound healing cascade, we used in vitro studies and an in vivo wound healing model to study whether shock wave treatment influences proliferation by altering major extracellular factors and signaling pathways involved in cell proliferation. We identified extracellular ATP, released in an energy-and pulse number-dependent manner, as a trigger of the biological effects of shock wave treatment. Shock wave treatment induced ATP release, increased Erk1/2 and p38 MAPK activation, and enhanced proliferation in three different cell types (C3H10T1/2 murine mesenchymal progenitor cells, primary human adipose tissue-derived stem cells, and a human JurkatTcell line) in vitro. Purinergic signaling-induced Erk1/2 activation was found to be essential for this proliferative effect, which was further confirmed by in vivo studies in a rat wound healing model where shock wave treatment induced proliferation and increased wound healing in an Erk1/2-dependent fashion. In summary, this report demonstrates that shock wave treatment triggers release of cellular ATP, which subsequently activates purinergic receptors and finally enhances proliferation in vitro and in vivo via downstream Erk1/2 signaling. In conclusion, our findings shed further light on the molecular mechanisms by which shock wave treatment exerts its beneficial effects. These findings could help to improve the clinical use of shock wave treatment for wound healing.