力敏感受体介导细胞功能调控的力学生物学研究

细胞膜是细胞与外部环境进行物质与能量交换的界面,是调节细胞正常生命活动的重要结构基础.细胞膜上力敏感受体可通过力学作用方式参与并影响细胞的力信号转导等功能.整合素和钙黏素是细胞膜上典型的力敏感受体,可介导细胞与细胞周围基质或邻近细胞发生力学作用,并将力学刺激信号转导为生化信号,进而激活细胞内一系列应答反应,最终影响细胞生长、分化、增殖、凋亡和迁移等功能.力敏感受体介导细胞功能调控研究已成为探索细胞主动响应外界复杂力学微环境的力学生物学机制的关键,为进一步深入认识生理和病理状态下细胞功能变化规律,为揭示疾病的发生、发展机制提供重要的力学生物学理论与实验依据.本文总结了力敏感受体介导细胞功能调控的国内外研究进展;介绍了黏附界面处典型力敏感受体的结构和功能;总结了这些力敏感受体参与的细胞力信号感知与响应的数理模型;概述了细胞通过力敏感受体进行力学信号转导的过程;介绍了黏附介导细胞功能调控的力学生物学过程和机制;简述了体外构建模拟细胞力学微环境中细胞-细胞外基质和细胞-细胞力学相互作用的技术;指出了力敏感受体介导细胞功能调控的力学生物学研究发展趋势和未来方向.     

细胞骨架生物力学进展

细胞骨架力学作为力学细胞生物学的一个新兴领域, 其研究方法突破传统细胞力学思想, 不再把活细胞简化为皮质膜包着的弹性、黏性或黏弹性连续介质体, 而是基于在细胞变形和功能中发挥重要作用的细胞骨架离散网络结构, 在微/纳米尺度建立一种集细胞形态和功能于一体的离散网络结构. 这种细胞骨架模型作为细胞变形和生化事件调控的纽带, 能从分子层次上阐述细胞运动、能量转换、信息传递、基因表达等重大生命活动的潜在机制,同时也能解释生物大分子间相互作用、受体/配体特异性相互作用、大分子自装配、细胞及分子层次的力学-化学耦合, 为定量研究细胞-亚细胞-生物大分子等在多种力学刺激下的响应建立了良好的平台, 对于理解生物模式形成、生物复杂性以及解决重大生物学难题具有深远意义. 本文基于细胞骨架三维离散网络结构特点及其生物学背景, 从生物力学角度详细阐述近几年国际上流行的细胞骨架模型理论分析和研究成果的最新进展.      

悬浮态上皮细胞粘附的力学-化学耦合模型及数值模拟

上皮细胞通过局部募集上皮性钙粘附蛋白 (E-cadherin) 建立胞间粘着连接, 实验证实该过程受到肌球蛋白皮层张力的调控. 为了从系统层面阐明粘着连接形成动力学过程, 本文考察皮层张力调控肌动蛋白 (F-actin) 解聚从而参与E-cadherin级联转导, 同时以马达-离合器机制模拟两细胞相互作用, 据此构建可反映悬浮态细胞粘附的力学-化学耦合数学模型; 对整体包含随机点源的非线性反应-扩散方程组与平衡微分方程耦合系统采取了自行发展的格子Boltzmann-粒子法与蒙特-卡洛法数值求解. 数值模拟表明, 由收缩性肌球蛋白 (myosin-II) 拉动胞间E-cadherin成键可提升皮层张力, 进而降低F-actin解聚速率﹑锚定更多的E-cadherin; 所构成的力学反馈回路展现出时空效应, 可帮助E-cadherin在接触区建立初始极性; E-cadherin形成顺式二聚体则将初始极性放大, 导致接触区E-cadherin展现起始、快速增长及慢速增长的积聚动力学特征. 皮层呈松散结构时刚度较小, 可通过延长胞间E-cadherin成键寿命提升张力, 而接触区弧度适中时($\approx$1.2 rad) E-cadherin峰值最高; 两者可分别作为启动力学反馈回路及调控粘着连接成熟度的有效手段.      

悬浮态上皮细胞粘附的力学-化学耦合模型及数值模拟

上皮细胞通过局部募集上皮性钙粘附蛋白(E-cadherin)建立胞间粘着连接,实验证实该过程受到肌球蛋白皮层张力的调控.为了从系统层面阐明粘着连接形成动力学过程,本文考察皮层张力调控肌动蛋白(F-actin)解聚从而参与E-cadherin级联转导,同时以马达-离合器机制模拟两细胞相互作用,据此构建可反映悬浮态细胞粘附的力学-化学耦合数学模型;对整体包含随机点源的非线性反应-扩散方程组与平衡微分方程耦合系统采取了自行发展的格子Boltzmann-粒子法与蒙特-卡洛法数值求解.数值模拟表明,由收缩性肌球蛋白(myosin-II)拉动胞间E-cadherin成键可提升皮层张力,进而降低F-actin解聚速率﹑锚定更多的E-cadherin;所构成的力学反馈回路展现出时空效应,可帮助E-cadherin在接触区建立初始极性; E-cadherin形成顺式二聚体则将初始极性放大,导致接触区E-cadherin展现起始、快速增长及慢速增长的积聚动力学特征.皮层呈松散结构时刚度较小,可通过延长胞间E-cadherin成键寿命提升张力,而接触区弧度适中时(≈1.2 rad) E-cadherin峰值最高;两者可分别作为启动力学反馈回路及调控粘着连接成熟度的有效手段.     

物理力学的产生及其发展

物理力学是近代力学一个新的分支,它是研究宏观力学现象的微观理论的学科。物理力学的基本目的是:从构成物质的微观粒子(如原子、分子、电子)的性质及其相互作用出发,找出介质和材料的宏观力学性质的计算方法,并且探讨力学运动规律的微观表述形 ...     

骨组织细胞的力学调控研究

力学环境是影响骨组织细胞形成、增殖和功能成熟的一个重要因素. 骨细胞是力学感受细胞, 将力学信号传递给效应细胞; 成骨细胞、破骨细胞为力学效应细胞, 使骨形成和骨吸收处于动态平衡以维持骨力学稳定性. 目前对骨组织细胞间力学调控的机理仍不甚清楚. 综述了骨组织细胞力学生物学作用和细胞间力学调控的一些相关问题. 在概述了成骨细胞、骨细胞和破骨细胞的生物学特性基础上,阐述了骨重建力学调控理论,成骨细胞、骨细胞和破骨细胞生物力学效应和细胞间力学调控最新研究进展. 最后对骨组织细胞三维网络间力学调控研究做出展望.     

干细胞的生物力学研究

干细胞生物力学作为生物力学的重要分支和前沿学科,近年来在力学-生物学、力学-化学耦合等方面取得了重大进展,已成为生物力学乃至生物医学工程最活跃的领域之一,并对发育生物学、干细胞生物学、组织修复、再生医学等相关领域产生重要影响.干细胞具有独特的力学性质,可感知、传递、转导和响应生理力学微环境的改变,从而调控干细胞的生长、分化等功能,体现出典型的力学-生物学耦合特征.本文将对干细胞的力学性质与细胞力学模型、在体力学环境对干细胞生长和分化的影响、干细胞对外界力学刺激的响应等方面加以综述.     

Biomechanics of stem cells

干细胞生物力学作为生物力学的重要分支和前沿学科,近年来在力学-生物学、力学-化学耦合等方面取得了重大进展,已成为生物力学乃至生物医学工程最活跃的领域之一,并对发生物学、干细胞生物学、组织修复、再生医学等相关领域产生重要影响.干细胞具有独特的力学性质,可感知、传递、转导和响应生理力学微环境的改变,从而调控干细胞的生长、分化等功能,体现出典型的力学-生物学耦合特征.本文将对干细胞的力学性质与细胞力学模型、在体力学环境对干细胞生长和分化的影响、干细胞对外界力学刺激的响应等方面加以综述.     

受体与配体结合的动力学研究进展

受体（Ｒｅｃｅｐｔｏｒ）与配体（Ｌｉｇａｎｄ）分子之间的结合是特异性的、可逆性的,其反应动力学特征通常用正向或逆向反应速度常数κｆ或κｒ,及亲和力κａ表示．κｆ与κｋｒ,可分别反映受体与配体结合与解离的速率, κａ＝ κｆ／κｒ,表示两者的结合能力．当受体或配体分子至少一种处于游离状态时,受体与配体之间的结合是三维的．目前,已有许多方法研究三维受体配体反应动力学．当受体配体均位于细胞表面时,受体与配体之间的结合则局限于两细胞之间的二维空间．很长时间以来,由于缺乏研究二维动力学的方法,故直到９０年代流动腔和微吸管技术的相继引入,关于受体配体结合动力学的研究才由三维转入到二维水平．二维动力学研究的指导思想是通过粘附概率与接触时间的相关性求得动力学参数．     

细胞牵引力显微镜反演方法研究进展

细胞与胞外基质微环境的物理力学相互作用涉及许多复杂的生物信号转导通路,对于细胞的增殖、分化、收缩、迁移和凋亡等都起着重要的调控作用.在单细胞水平上,运用细胞牵引力显微镜方法定量研究细胞活动规律及特点具有重要的生理病理学意义.牵引力显微镜方法的核心在于如何通过基底变形信息反演得到细胞牵引力场.本文首先介绍细胞牵引力反演方...     

Probing the mechanosensitivity in cell adhesion and migration: Experiments and modeling

Cell adhesion and migration are basic physiological processes in living organisms. Cells can actively probe their mechanical micro-environment and respond to the external stimuli through cell adhesion. Cells need to move to the targeting place to perform function via cell migration. For adherent cells, cell migration is mediated by cell-matrix adhesion and cell-cell adhesion. Experimental approaches, especially at early stage of investigation, are indispensable to studies of cell mechanics when even qualitative behaviors of cell as well as fundamental factors in cell behaviors are unclear. Currently, there is increasingly accumulation of experimental data of measurement, thus a quantitative formulation of cell behaviors and the relationship among these fundamental factors are highly needed. This quantitative understanding should be crucial to tissue engineering and biomedical engineering when people want to accurately regulate or control cell behaviors from single cell level to tissue level. In this review, we will elaborate recent advances in the experimental and theoretical studies on cell adhesion and migration, with particular focuses laid on recent advances in experimental techniques and theoretical modeling, through which challenging problems in the cell mechanics are suggested.     

细胞铺展动力学的研究进展

细胞与细胞外基质之间的相互作用在细胞的迁移、分化、凋亡等生理过程中起着重要的作用,细胞铺展作为细胞与细胞外基质作用的第1步,受到了人们的广泛关注.首先阐述了细胞铺展的关键生物动力学过程,对铺展3个不同阶段的特点进行了总结和归纳,并运用力学的观点阐明了细胞铺展的驱动力及驱动机制,详细讨论了聚合力、黏附力以及细胞张力等3种主要作用力在细胞铺展过程中的作用规律以及相应的物理模型.在此基础上,从细胞的黏性流动及力学平衡两个方面出发,简要综述了已有相关研究结果的不足之处,介绍了当前建立细胞铺展动力学模型的主要思路,并探讨了今后面向细胞生物学需求的相关细胞动力学的研究方向.      

Specific adhesion of vesicles to compliant bio-adhesive substrates

Cell behavior is mediated by variety of physiochemical properties of the extracellular matrix (ECM). Mechanical stiffness of ECM, in particular, is found to be a major regulator for the multiple aspects of cellular function. Experiments show that cells generally exhibit an apparent adhesion preference for stiffer substrates. The effect of substrate elasticity is also found to be strongly coupled with adhesivity of the substrate. To understand the underlying physics of rigidity sensing mechanism in cells, in this study we use a vesicle-substrate system to model cell adhesion as a first order approximation. Within this framework, an equilibrium thermodynamic analysis is undertaken to elucidate the interplay between substrate compliance and equilibrium configuration of an adherent vesicle. The equilibrium adhesion is assumed to ensure minimization of the free energy contributed by substrate deformation and interfacial adhesive and repulsive interactions between the membrane and substrate. The predictions of this purely mechanistic model are found to be qualitatively analogous to some of the characteristic features of cell adhesion to compliant bio-adhesive substrates. This observation suggests that the physical aspects of the membrane–substrate interfacial interactions could passively contribute in regulation of the rigidity sensing by cells.     

Mechanokinetics of receptor–ligand interactions in cell adhesion

Receptor-ligand interactions in blood flow are crucial to initiate such biological processes as inflammatory cascade,platelet thrombosis,as well as tumor metastasis.To mediate cell adhesion,the interacting receptors and ligands must be anchored onto two apposing surfaces of two cells or a cell and a substratum,i.e.,two-dimensional(2D)binding,which is different from the binding of a soluble ligand in fluid phase to a receptor,i.e.,three-dimensional(3D) binding.While numerous works have been focused on3 D kinetics of receptor-ligand interactions in the immune system,2D kinetics and its regulations have been less understood,since no theoretical framework or experimental assays were established until 1993.Not only does the molecular structure dominate 2D binding kinetics,but the shear force in blood flow also regulates cell adhesion mediated by interacting receptors and ligands.Here,we provide an overview of current progress in 2D binding and regulations,mainly from our group.Relevant issues of theoretical frameworks,experimental measurements,kinetic rates and binding affinities,and force regulations are discussed.     

A dynamic cellular vertex model of growing epithelial tissues

Intercellular interactions play a significant role in a wide range of biological functions and processes at both the cellular and tissue scales, for example, embryogenesis, organogenesis, and cancer invasion. In this paper, a dynamic cellular vertex model is presented to study the morphome-chanics of a growing epithelial monolayer. The regulating role of stresses in soft tissue growth is revealed. It is found that the cells originating from the same parent cell in the monolayer can orchestrate into clustering patterns as the tis-sue grows. Collective cell migration exhibits a feature of spatial correlation across multiple cells. Dynamic intercel-lular interactions can engender a variety of distinct tissue behaviors in a social context. Uniform cell proliferation may render high and heterogeneous residual compressive stresses, while stress-regulated proliferation can effectively release the stresses, reducing the stress heterogeneity in the tissue. The results highlight the critical role of mechanical factors in the growth and morphogenesis of epithelial tissues and help understand the development and invasion of epithelial tumors.     

ADVANCES IN EXPERIMENTAL APPROACHES FOR INVESTIGATING CELL AGGREGATE MECHANICS

Cells tend to form hierarchy structures in native tissues.Formation of cell aggregates in vitro such as cancer spheroids and embryonic bodies provides a unique means to study the mechanical properties and biological behaviors/functions of their counterparts in vivo.In this paper,we review state-of-the-art experimental approaches to assess the mechanical properties and mechanically-induced responses of cell aggregates in vitro.These approaches are classified into five categories according to loading modality,including micropipette aspiration,centrifugation,compression loading,substrate distention,and fluid shear loading.We discussed the advantages and disadvantages of each approach,and the potential biomedical applications.Understanding of the mechanical behavior of cell aggregates provides insights to physical interactions between cells and integrity of biological functions,which may enable mechanical intervention for diseases such as atheromatosis and cancer.     

Engineering mechanical-electrical cell microenvironment in myocardium using advanced biomaterials

心血管疾病是当前全球范围内导致人类死亡的首要原因, 心肌组织工程的发展为心血管疾病的治疗, 尤其是心肌组织再生修复提供了最有潜力的解决方案.心血管疾病的发生发展与细胞力--电微环境的变化密切相关. 近十几年, 随着先进生物材料和微纳生物制造技术的发展, 越来越多的研究表明, 细胞力--电微环境的调控对工程化心肌组织的成熟和功能化以及心肌组织再生修复具有重要意义. 本文首先阐明了在体心肌细胞所处力学微环境的生物学基础以及电信号的传导过程, 包括正常和疾病状态下心肌细胞所处的力--电微环境.其次调研了用于心肌组织工程的先进生物材料的研究现状.最后总结用于基底硬度与应力应变细胞微环境以及细胞电学微环境的构建和调控, 以及细胞对力--电微环境的生物学响应.%     

Pollen tube growth: Getting a grip on cell biology through modeling

Cellular growth in plant, fungal and bacterial cells is based on the mechanical deformation of the cellular envelope by the hydrostatic turgor pressure. Shape generation is therefore a mechanical problem whose biological control is poorly understood. The pollen tube is an attractive model system for the investigation of the growth process in walled cells. The geometry, mechanics and kinetics of the growth process represent intriguing features that are well investigated experimentally. In particular, the presence of regular pulsations in the growth rate, an indicator of non-linear feedback regulation, has attracted the attention of modelers from the engineering, mathematical and physical communities. Here, we summarize important hallmarks characterizing pollen tube growth, and we illustrate how modeling and mathematical analysis have become an integral part of the research programs targeting this cell type.     

基于先进生物材料的心肌细胞力——电微环境体外构建

心血管疾病是当前全球范围内导致人类死亡的首要原因, 心肌组织工程的发展为心血管疾病的治疗, 尤其是心肌组织再生修复提供了最有潜力的解决方案.心血管疾病的发生发展与细胞力--电微环境的变化密切相关. 近十几年, 随着先进生物材料和微纳生物制造技术的发展, 越来越多的研究表明, 细胞力--电微环境的调控对工程化心肌组织的成熟和功能化以及心肌组织再生修复具有重要意义. 本文首先阐明了在体心肌细胞所处力学微环境的生物学基础以及电信号的传导过程, 包括正常和疾病状态下心肌细胞所处的力--电微环境.其次调研了用于心肌组织工程的先进生物材料的研究现状.最后总结用于基底硬度与应力应变细胞微环境以及细胞电学微环境的构建和调控, 以及细胞对力--电微环境的生物学响应.%