Aberrant mechanosensing in injured intervertebral discs as a result of boundary-constraint disruption and residual-strain loss
Aberrant mechanosensing in injured intervertebral discs as a result of boundary-constraint disruption and residual-strain loss
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DOI：
10.1038/s41551-019-0458-4
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发表时间：
2019-12-01
影响因子：
28.1
通讯作者：
Mauck, Robert L.
中科院分区：
文献类型：
--
作者：
Bonnevie, Edward D.;Gullbrand, Sarah E.;Mauck, Robert L.
在纤维组织中，骨界面处的预应力边界约束会在整个组织中产生残余应变，即使在卸载时也是如此。例如，椎间盘中央髓核中的内部膨胀压力在外纤维环中产生预应变。随着损伤和减压，这些残余应变就会消失。在这里，我们证明椎间盘中残余应变的损失会改变微环境并引发异常的组织重塑和非典型细胞表型的采用。通过使用兔子纤维环的穿刺手术、离体穿刺实验和电纺纳米纤维支架来概括这些不断变化的边界约束，我们表明残余应变的损失促进了短期细胞凋亡和纤维化表型的出现。我们还表明，局部纤维组织和细胞收缩性介导这一过程，并且通过用小分子靶向细胞机械传感机制可以消除异常的细胞变化。我们的研究结果表明，预应变下致密结缔组织的损伤会改变边界约束和残余应变；这会导致机械传感异常，进而促进疾病进展。
In fibrous tissues, prestressed boundary constraints at bone interfaces instil residual strain throughout the tissue, even when unloaded. For example, internal swelling pressures in the central nucleus pulposus of the intervertebral disc generate prestrain in the outer annulus fibrosus. With injury and depressurization, these residual strains are lost. Here we show that the loss of residual strains in the intervertebral disc alters the microenvironment and instigates aberrant tissue remodelling and the adoption of atypical cellular phenotypes. By using puncture surgery of the annulus fibrosus in rabbits, ex vivo puncture experiments and electrospun nanofibrous scaffolds recapitulating these evolving boundary constraints, we show that the loss of residual strain promotes short-term apoptosis and the emergence of a fibrotic phenotype. We also show that local fibre organization and cellular contractility mediate this process and that the aberrant cellular changes could be abrogated by targeting the cell-mechanosensing machinery with small molecules. Our findings indicate that injury to dense connective tissues under prestrain alters boundary constraints and residual strain; this leads to aberrant mechanosensing, which in turn promotes disease progression.