邓林红教授继Nature文章后再次解析细胞力学研究

　　

    近日，重庆大学生物工程学院邓林红教授实验室与美国哈佛大学合作实验室在国际著名开放读取综合学术杂志Plos One上发表论文，揭示机械拉伸引发细胞流态化响应的内在机制。

    该合作研究是邓林红教授于与哈佛大学合作者继2007年在Nature上发表有关机械拉伸引起细胞流态化响应论文后的进一步深化（Universal physical responses to stretch in the living cell”——Nature 447:592-595, 31 May, 2007）。2007年发表在Nature上的论文首次提出了活细胞在收到短暂机械牵张之后会迅速软化并向流体状态转化，随后又逐渐恢复到拉伸前的状态。这一现象在各种细胞和生化环境下都有普遍性，因此对于理解细胞的物理行为和相关生理病理现象具有十分重要的意义。但该重要现象的内在机制仍然没有得到完全的揭示。

   2008年10月，邓林红教授的博士研究生陈诚作为重庆大学和美国哈佛大学联合培养的博士研究生，被派往哈佛大学，在美方共同导师Fredberg教授的实验室继续有关细胞在机械拉伸后发生流态化及其内在机制的研究。经过近两年的努力，陈诚在中美双方导师的共同指导和和其他合作者的通力协作下，利用细胞牵张力显微测量技术，磁微粒扭转细胞流变测量技术等细胞力学领域先进技术动态观测了人体膀胱平滑肌细胞在受到短暂的机械牵张后，其细胞硬度、细胞牵张力、以及细胞骨架形态的变化。

    实验结果表明，膀胱平滑肌细胞在受到短暂牵张之后迅速“液化”，然后缓慢的“再固化”，逐渐恢复到拉伸前的状态。更为重要的是，由于短暂拉伸持续的时间非常短，细胞发生的所有物理相应过程并不是通过细胞内部的生物化学信号通路调控的，而是通过细胞骨架的纤维型肌动蛋白（F-actin）的迅速分解和缓慢再重组来实现和调控的。

   Plos One发表的这篇论文，不仅采用人体内另一种同样收到机械牵张力的影响的膀胱平滑肌细胞进一步证实了细胞在受到短暂拉伸后迅速发生流态化与缓慢恢复的普遍性，并且找出首次观测到了F-actin在其中扮演的关键作用，至少部分地，如果不是完全的话，揭示了这个现象的内在物理调控机制。

    随着现代细胞生物学和细胞动力学的共同发展，机械力和物理环境如何对细胞结构和功能发生影响并决定许多重大生命活动过程的谜团正在被逐步打开。因此，在对细胞进行传统的生物分析和化学分析的同时，系统地研究细胞的物理环境和受力情况以及相应的细胞行为规律，将对更准确、更深入地理解细胞的运作机制、为细胞生理学和病理学的研究提供新的启发和思路。

原文摘要：PLoS ONE 5(8): e12035. doi:10.1371/journal.pone.0012035

在线链接：http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0012035

Fluidization and Resolidification of the Human Bladder Smooth Muscle Cell in Response to Transient Stretch

Cheng Chen1,2#, Ramaswamy Krishnan2#, Enhua Zhou2, Aruna Ramachandran3, Dhananjay Tambe2, Kavitha Rajendran2, Rosalyn M. Adam3, Linhong Deng1,2*, Jeffrey J. Fredberg2

1 Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing, China, 2 Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, United States of America, 3 Urological Diseases Research Center, Department of Urology, Children's Hospital Boston and Department of Surgery, Harvard Medical School, Boston, Massachusetts, United States of America

Abstract
Background：Cells resident in certain hollow organs are subjected routinely to large transient stretches, including every adherent cell resident in lungs, heart, great vessels, gut, and bladder. We have shown recently that in response to a transient stretch the adherent eukaryotic cell promptly fluidizes and then gradually resolidifies, but mechanism is not yet understood.
Principal Findings：In the isolated human bladder smooth muscle cell, here we applied a 10% transient stretch while measuring cell traction forces, elastic modulus, F-actin imaging and the F-actin/G-actin ratio. Immediately after a transient stretch, F-actin levels and cell stiffness were lower by about 50%, and traction forces were lower by about 70%, both indicative of prompt fluidization. Within 5min, F-actin levels recovered completely, cell stiffness recovered by about 90%, and traction forces recovered by about 60%, all indicative of resolidification. The extent of the fluidization response was uninfluenced by a variety of signaling inhibitors, and, surprisingly, was localized to the unstretch phase of the stretch-unstretch maneuver in a manner suggestive of cytoskeletal catch bonds. When we applied an “unstretch-restretch” (transient compression), rather than a “stretch-unstretch” (transient stretch), the cell did not fluidize and the actin network did not depolymerize.
Conclusions：Taken together, these results implicate extremely rapid actin disassembly in the fluidization response, and slow actin reassembly in the resolidification response. In the bladder smooth muscle cell, the fluidization response to transient stretch occurs not through signaling pathways, but rather through release of increased tensile forces that drive acute disassociation of actin.

通讯作者介绍：
姓 名: 邓林红，博士(英国斯查克莱大学生物工程)、教授、博导
联系地址: 重庆市沙坪坝区沙坪正街174号
重庆大学生物工程学院316
邮政编码：400044
电 话: [phone];
传 真: [phone];
电子邮箱 : [e-mail]

教育部“****奖励计划”特聘教授
重庆大学生物工程学院特聘教授
重庆大学“国家985工程”科技创新平台－生物流变学与基因调控新技术研究院院长
美国哈佛大学公共卫生学院客座科学家
重庆大学生物医学工程国家一级重点学科带头人
重庆市生物医学工程学科带头人
重庆市首批高校创新团队负责人、
美国纽约科学院会员
中国生物物理学会理事
中国光学会生物医学光子学专业委员会常务委员
中国生物材料学会会员
主要获奖：
2010 中国侨界（创新人才）贡献奖
2008 汤姆森科技《科学观察》世界材料科学领域“快速突破论文”
2003 美国实验生物学联合会“平滑肌研究青年科学家奖”
1992 国际生物流变学会旅行奖

主要学术论文
1. Chen C, Krishnan R, Zhou E,…Deng, L., Fredberg, JJ. (2010) Fluidization and Resolidification of the Human Bladder Smooth Muscle Cell in Response to Transient Stretch. PLoS ONE 5(8): e12035. doi:10.1371/journal.pone.0012035
2. Deng, L, et al. Stress and strain in airway smooth muscle filaments. Pulmonary Pharmacology and Therapeutics, 22:407-416,2008
3. Nigel J. Fairbank, Sarah C.Connolly, Linhong Deng, Geoffrey N.Maksym. Airway smooth muscle cell tone amplifies contractile function in the presence of chronic cyclic strain. Am J Physiol Lung Cell Mol Physiol, 295(3): L479-488, 2008
4. Cai Kaiyong, Yan Hu,….Linhong Deng. Cell-Specific Gene Transfection from a Gene-Functionalized Poly(lactic acid) Substrate Fabricated by the Layer-by-Layer Assembly Technique. Angewandte Chemie, 47(39):7479-7481,2008
5. Deng, Linhong., Dynamics of the cytoskeleton: A portrait of living cells as heterogeneous and nonequilibrial materials, in Advances in Heterogeneous Material Mechanics, DESTECH PUBLICATIONS INC: Lancaster. p. 582-587, 2008.
6. Trepat Xavier, Linhong Deng, Steve S. An, Daniel Nevajas, Daniel J Tschumperlin, Willliam T. Gerthoffer, James P. Butler, and Jeffrey J. Fredberg. Universal physical responses to stretch in the living cell. Nature 447:592-595, 31 May, 2007
7. An SS, Bai TR, ….Deng L, et al. Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma. European Respiratory J 29:834-860, 2007
8. Cai Kaiyong, Jun Zhang，Linhong Deng, Li Yang, Yan Hu, Lei Xu. Physical and biological properties of a novel hydrogel composite based on oxidized alginate, gelatin and tricalcium phosphate for bone tissue engineering. Advanced Engineering Materials. Vol. 9:1082-1088, 2007
9. Deng, Linhong Xavier Trepat, James P. Butler, Emil Millet, Kathleen G. Morgan, David A. Weitz and Jeffrey J. Fredberg. Fast and slow dynamics of the cytoskeleton. Nature Materials 5:636-640, 2006
10. Deng, L, NJ Fairbank, DJ Cole, JJ Fredberg and GN Maksym. Airway smooth muscle tone modulates mechanically induced cytoskeletal stiffening and remodeling. J Appl Physiol 99: 634-641, 2005.
11. Maksym, GN, Deng, L, Fairbank, NJ, Lall, CA, and SC Connoly: Beneficial and harmful effects of oscillatory mechanical strain on airway smooth muscle. Canadian Journal of physiology and Pharmacology 83:913-922, 2005.
12. Bai TR, … Deng LH, et al. On the terminology for describing the length-force relationship and its changes in airway smooth muscle. J Appl Physiol. 97(6):2029-34, 2004 (An invited editorial)
13. Deng, L, NJ Fairbank, B Fabry, PG Smith, GN Maksym. Localized mechanical stress induces time-dependent actin cytoskeletal remodeling and stiffening in cultured airway smooth muscle cells. Am J Physiol: Cell Physiol. 287: C440-448, 2004
14. Smith, P.G., Deng, L., Fredberg, J.J. and G.N. Maksym: Mechanical Strain Increases Cell Stiffness Through Cytoskeletal Filament Reorganization. American Journal of Physiology: Lung Cellular and Molecular Physiology 285(2):L456-63, 2003