Effects of Intermittent and Incremental Cyclic Stretch on ERK Signaling and Collagen Production in Engineered Tissue.
Effects of Intermittent and Incremental Cyclic Stretch on ERK Signaling and Collagen Production in Engineered Tissue.
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DOI：
10.1007/s12195-015-0415-6
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发表时间：
2016-03-01
影响因子：
2.8
通讯作者：
Tranquillo RT
中科院分区：
文献类型：
--
作者：
Schmidt JB;Chen K;Tranquillo RT
探索了间歇性循环拉伸和逐渐增加应变幅度循环拉伸，以克服已报道的成纤维细胞对恒定振幅循环拉伸的适应，目的是加速胶原蛋白的产生并了解潜在的细胞信号传导。通过监测细胞外信号调节激酶 (ERK1/2) 和 p38 通路、胶原蛋白转录以及最终沉积的胶原蛋白，研究恒定幅度、间歇性和增量循环拉伸方案对纤维蛋白凝胶中包埋的真皮成纤维细胞的影响。 ERK1/2 的激活已被证明是拉伸诱导的胶原蛋白转录所必需的，在 15 分钟时达到最大，并在 1 小时内衰减。 ERK1/2 通过额外的拉伸开始或初始刺激后 6 小时应变幅度的增加而重新激活，这大约是激活的 p38（一种已知的 ERK1/2 抑制剂）的寿命。虽然间歇性拉伸和增量拉伸方案都会重新激活 ERK1/2，但与恒定幅度拉伸的样品相比，只有增量拉伸才能增加胶原蛋白的产生，导致 2 周后每个细胞的胶原蛋白增加 37%。这表明应变幅度小而频繁增量的方案对于该系统是最佳的，并且应该用于需要高胶原含量的工程组织的生物反应器中。
Intermittent cyclic stretching and incrementally increasing strain amplitude cyclic stretching were explored to overcome the reported adaptation of fibroblasts in response to constant amplitude cyclic stretching, with the goals of accelerating collagen production and understanding the underlying cell signaling. The effects of constant amplitude, intermittent, and incremental cyclic stretching regimens were investigated for dermal fibroblasts entrapped in a fibrin gel by monitoring the extracellular signal-regulated kinase (ERK1/2) and p38 pathways, collagen transcription, and finally the deposited collagen protein. Activation of ERK1/2, which has been shown to be necessary for stretch-induced collagen transcription, was maximal at 15 min and decayed by 1 h. ERK1/2 was reactivated by an additional onset of stretching or by an increment in the strain amplitude 6 h after the initial stimulus, which was approximately the lifetime of activated p38, a known ERK1/2 inhibitor. While both intermittent and incremental regimens reactivated ERK1/2, only incremental stretching increased collagen production compared to samples stretched with constant amplitude, resulting in a 37% increase in collagen per cell after 2 weeks. This suggests that a regimen with small, frequent increments in strain amplitude is optimal for this system and should be used in bioreactors for engineered tissues requiring high collagen content.