局部机械刺激与蝾螈关节形态发生中的组织生长相关。
Local mechanical stimuli correlate with tissue growth in axolotl salamander joint morphogenesis.
机构信息
Serra Húnter Fellow, Department of Physics, Universitat Politècnica de Catalunya (UPC), Barcelona, Spain.
Department of Mechanical and Industrial Engineering, Northeastern University, Boston, MA USA.
出版信息
Proc Biol Sci. 2022 May 25;289(1975):20220621. doi: 10.1098/rspb.2022.0621. Epub 2022 May 18.
Movement-induced forces are critical to correct joint formation, but it is unclear how cells sense and respond to these mechanical cues. To study the role of mechanical stimuli in the shaping of the joint, we combined experiments on regenerating axolotl () forelimbs with a poroelastic model of bone rudiment growth. Animals either regrew forelimbs normally (control) or were injected with a transient receptor potential vanilloid 4 (TRPV4) agonist during joint morphogenesis. We quantified growth and shape in regrown humeri from whole-mount light sheet fluorescence images of the regenerated limbs. Results revealed significant differences in morphology and cell proliferation between groups, indicating that TRPV4 desensitization has an effect on joint shape. To link TRPV4 desensitization with impaired mechanosensitivity, we developed a finite element model of a regenerating humerus. Local tissue growth was the sum of a biological contribution proportional to chondrocyte density, which was constant, and a mechanical contribution proportional to fluid pressure. Computational predictions of growth agreed with experimental outcomes of joint shape, suggesting that interstitial pressure driven from cyclic mechanical stimuli promotes local tissue growth. Predictive computational models informed by experimental findings allow us to explore potential physical mechanisms involved in tissue growth to advance our understanding of the mechanobiology of joint morphogenesis.
运动引起的力对于正确的关节形成至关重要,但目前尚不清楚细胞如何感知和响应这些机械线索。为了研究机械刺激在关节形成中的作用,我们将再生蝾螈()前肢的实验与骨原基生长的多孔弹性模型相结合。动物要么正常再生前肢(对照),要么在关节形态发生期间注射瞬时受体电位香草酸 4(TRPV4)激动剂。我们通过再生肢体的全层光片荧光图像定量测量了再生肱骨的生长和形状。结果显示,两组之间的形态和细胞增殖存在显著差异,表明 TRPV4 脱敏对关节形状有影响。为了将 TRPV4 脱敏与机械敏感性受损联系起来,我们开发了一个再生肱骨的有限元模型。局部组织生长是与软骨细胞密度成正比的生物学贡献与与流体压力成正比的机械贡献之和,而生物学贡献是恒定的。生长的计算预测与关节形状的实验结果一致,表明由周期性机械刺激驱动的间质压力促进了局部组织生长。受实验结果启发的预测计算模型使我们能够探索组织生长中涉及的潜在物理机制,从而深入了解关节形态发生的机械生物学。