Tissue Strain Reorganizes Collagen With a Switchlike Response That Regulates Neuronal Extracellular Signal-Regulated Kinase Phosphorylation In Vitro: Implications for Ligamentous Injury and Mechanotransduction.
Tissue Strain Reorganizes Collagen With a Switchlike Response That Regulates Neuronal Extracellular Signal-Regulated Kinase Phosphorylation In Vitro: Implications for Ligamentous Injury and Mechanotransduction.
复制标题
组织应变通过开关样反应重组胶原蛋白，调节神经元细胞外信号调节激酶体外磷酸化：对韧带损伤和机械转导的影响。
DOI：
10.1115/1.4031975
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Winkelstein,BethA
中科院分区：
文献类型：
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作者：
Zhang,Sijia;Cao,Xuan;Stablow,AlecM;Shenoy,VivekB;Winkelstein,BethA
韧带的过度负荷可以激活神经传入，神经支配胶原组织，导致包括疼痛在内的一系列病理。一个综合的实验和建模方法被用来定义神经元和周围的胶原纤维的韧带基质负载的反应，并开始理解宏观变形是如何被翻译为神经元的负载和信号。神经元胶原结构（NCC）模拟神经支配的胶原组织进行张力应变模拟无痛（8%）或疼痛韧带负荷（16%）。细胞外信号调节激酶（ERK）的神经元磷酸化与神经可塑性（R2≥ 0.041; p ≤ 0.0171）和神经元纵横比（AR）（R2≥ 0.250; p < 0.0001）相关，与组织水平的菌株显著相关。随着NCC应变在缓慢施加负荷（1%/s）期间增加，检测到“开关样”纤维重新排列反应，胶原重组仅发生在11.3%应变的转变点以上。基于有限元的离散纤维网络（DFN）模型预测，在高于转变点的体应变处，异质纤维应变是拉伸和压缩的并且增加，其中一些纤维中的应变沿着加载方向超过所施加的体应变。胶原纤维重新排列变化的转变点与负荷后ERK磷酸化升高的应变阈值（11.7%，95%置信区间为10.2-13.4%）一致。与胶原纤维重新排列一样，在NCC牵引处观察到最大程度的神经元向负荷方向的重新定向，对应于疼痛负荷。由于神经元ERK的激活只发生在产生明显的胶原纤维重新排列的菌株，研究结果表明，组织应变引起的微机械环境的变化，特别是改变局部胶原纤维运动学，可能与神经元中的mechanodonduction信号。
Excessive loading of ligaments can activate the neural afferents that innervate the collagenous tissue, leading to a host of pathologies including pain. An integrated experimental and modeling approach was used to define the responses of neurons and the surrounding collagen fibers to the ligamentous matrix loading and to begin to understand how macroscopic deformation is translated to neuronal loading and signaling. A neuron-collagen construct (NCC) developed to mimic innervation of collagenous tissue underwent tension to strains simulating nonpainful (8%) or painful ligament loading (16%). Both neuronal phosphorylation of extracellular signal-regulated kinase (ERK), which is related to neuroplasticity (R2≥ 0.041; p ≤ 0.0171) and neuronal aspect ratio (AR) (R2≥ 0.250; p < 0.0001), were significantly correlated with tissue-level strains. As NCC strains increased during a slowly applied loading (1%/s), a “switchlike” fiber realignment response was detected with collagen reorganization occurring only above a transition point of 11.3% strain. A finite-element based discrete fiber network (DFN) model predicted that at bulk strains above the transition point, heterogeneous fiber strains were both tensile and compressive and increased, with strains in some fibers along the loading direction exceeding the applied bulk strain. The transition point identified for changes in collagen fiber realignment was consistent with the measured strain threshold (11.7% with a 95% confidence interval of 10.2–13.4%) for elevating ERK phosphorylation after loading. As with collagen fiber realignment, the greatest degree of neuronal reorientation toward the loading direction was observed at the NCC distraction corresponding to painful loading. Because activation of neuronal ERK occurred only at strains that produced evident collagen fiber realignment, findings suggest that tissue strain-induced changes in the micromechanical environment, especially altered local collagen fiber kinematics, may be associated with mechanotransduction signaling in neurons.