• basic
    • Mechanisms by which cells convert a mechanical stimulus into a chemical signal
    • Cells possess many mechanosensitive entities机械敏感实体 on their surface such as
      • Mechanosensitive ion channels 机械敏感离子通道
      • G-protein coupled or grow factor receptor G蛋白偶联或生长因子受体
      • Extracellular matrix binding receptors 细胞外基质结合受体
      • Cell-cell binding molecules 细胞间结合分子
      • Cryptic Binding Sites 隐蔽结合位点
      • 图
  • Mechanosensitive Ion Channels
    • divided into two categories by the force vector the channels respond
      根据其响应的力向量分为两类
      • force perpendicular to the lipid bilayer
        垂直于脂质双层的力
        • eg. Ca2+ ear hair cell channels
          Ca²⁺ 耳毛细胞通道
      • force parallel/in plan with the lipid bilayer
        与脂质双层平行 / 共面的力
        • eg. bacteria mechanosensitive K+ channel
          细菌机械敏感钾离子通道
  • Menchanosensing via ECM-cell adhesion
    FA
    • basic
      • External mechanical strains can be transmitted through ECM-integrin adhesions细胞外基质 - 整合素黏附 to modulate intracellular molecules, such as focal adhesion kinase 黏着斑激酶(FAK)
      • These molecular changes initiate a cascade of signaling events including the activation of Rho-family GTPases, such as RhoA
      • Rho-family GTPases promotes actin restructuring肌动蛋白重构, induces protein phosphorylation, and regulates gene expression by influencing transcription factors
      • Because mechanical signals propagate through long distances via physical cellular structures in the cells, the speed of the mechanically induced signaling is significantly faster compared to signaling mediated by diffusion of soluble factors
    • Cytoskeleton
      • The cytoskeleton is responsible for holding the shape and structure of the cell and protecting it, and it also helps with movement and stability.
      • The cytoskeleton is made up of microfilaments, microtubules, and intermediate filaments.
      • Microfilaments are about 3-6 nm diameter thread like fibers that are made up of actin (most abundant cell protein)
    • Focal adhesion (FA) complexes
      • The focal adhesion (FA) complexes consist of cluster of integrins and several cytoplasmic adaptor proteins, including vinculin and talin, which connects the intracellular domain of integrins to actomyosin cytoskeleton.
      • FAs serve as the link between the ECM and the intracellular cytoskeleton and allow transmission of mechanical signals from outside into the cellular space
      • FAs are dynamic and external forces can lead to conformational changes in FA proteins, such as talin and integrin, effectively converting mechanical signals into biochemical ones
    • Talin contains cryptic binding sites for Vinculin
      • talin就像一个很长的绳子折叠起来, 力作用使绳子会展开露出vinculin结合位点, 结合后promotes the clustering of integrins, 增强mechanotransduction
      • Talin is a large protein capable of creating a physical link of the cellular cytoskeleton to the ECM by interacting via its N-terminal domain with the tail of integrin Beta1 and attachment to actin with its C-terminal 5 helical bundle.
      • Between the binding domains is a flexible talin rod domain consisting of 11 vinculin binding sites, majority of which are buried within the amphipathic两亲性 helical bundle.
      • Physiological force generated across a focal adhesion results in the unfolding of the talin rod domain exposing cryptic sites for the vinculin head domain to bind. 黏着斑处产生的生理力会导致踝蛋白talin杆状结构域解折叠，暴露隐藏位点供黏着斑蛋白vinculin头部结构域结合
      • Talin–vinculin binding promotes the clustering of integrins, which further enhances the effect of mechanotransduction
  • Menchanosensing via cell-cell adhesion
    adherens junctions (AJ), tight junctions and gap junctions
    • Cell-cell adhesions, including adherens junctions (AJ), tight junctions and gap junctions, also play an important role in mechanotransduction
    • adherens junctions
      • AJs can directly transmit external mechanical signals into intracellular actomyosin肌动球蛋白 activities
      • AJs are mediated by the homotypic binding of extracellular domains of cadherins
      • cadherins is a family of transmembrane Ca2+-dependent adhesion molecules, expressed on the surfaces of the neighboring cells
      • 黏着连接 (AJ) 由钙黏蛋白家族的胞外域同型结合介导，该家族是表达于相邻细胞表面的跨膜钙依赖性黏附分子
      • Upon formation of AJs, scaffolding proteins are recruited by the cytoplasmic domains of cadherins and help anchor the actin cytoskeleton.
      • 黏着连接 (AJ) 形成后，钙黏蛋白的胞质域会招募支架蛋白，助力锚定肌动蛋白细胞骨架
  • FA(ECM-cell) and AJ(cell-cell) 的相同点以及后续信号转导
    • 跨膜受体转导力学到骨架
      • Both are formed by transmembrane receptors that are capable of transmitting external mechanical signals to intracellular actin cytoskeleton
        都是跨膜受体, 可以转导力学信号到细胞骨架
      • the transmembrane receptors form clusters and recruit signaling and structural molecules that can interact with action skeleton with their intracellular domains
        这些跨膜受体成簇, 并通过胞内域召集与骨架交互的蛋白
      • many of these recruited intracellular proteins, are shared by these two types of adhesions such as vinculin
        这些被招募的胞内蛋白中，有许多是这两种黏附类型共有的，例如黏着斑蛋白
    • 都用RhoA pathways 帮助机械信号转导
      • Adhesions activate pathways such as RhoA signaling pathway
      • RhoA signaling pathway promote cytoskeletal contractility收缩能力 and transmission of tension张力传递
      • RhoA, through its effector Rho kinase (Rock), plays a key role in the formation of stress fibers应力纤维 and generation of cytoskeletal tension细胞骨架张力 in adherent贴壁的 cells
        Rock是RhoA下游的发挥作用的分子
      • 图
    • 都用LINC 实现 mechanotransduction into nucleus
      • LINC (linker of nucleoskeleton and cytoskeleton) complex, which helps anchor cytoskeletal structures such as actin filaments to the nuclear membrane.
      • The LINC complex contains adaptor molecules such as nesprins, Sun and lamin proteins
      • Mechanical signals propagating through cytoskeleton and then the LINC complex can directly impact crucial DNA regulatory enzymes and binding factors via the interconnected nuclear scaffold核骨架
  • Diseases associated with defects in mechanotransduction
    • 图
  • Role of mechanical cues in developmental biology
    • Cell behavior and therefore tissue morphogenesis are strongly influenced by the mechanical signals from the environment such as compression, tension, fluid shear流体剪切力 etc.
    • Especially true for skeletogenesis
      肌肉的力对于骨骼发展至关重要
      • immobilization固定 of chick embryos using neuromuscular blocking agents abrogates废除 muscle dynamic contractions and lower muscle forces
      • 使用神经肌肉阻滞剂固定鸡胚会废除肌肉的动态收缩，降低肌肉力量
      • This induced paralysis had a dramatic effect on animal bone development 这种诱导性麻痹会对动物骨骼发育产生显著影响 and resulted in abnormal curvature, reduced size, or retarded延迟 growth in many bones like the mandible, neck and spine, femur, tibia, and humerus
      • Development of joints like the knee, ankle, hip and toe joints was minimal or absent in animal treated with drugs that blocked muscle contraction.
      • 经肌肉收缩阻断药物处理的动物，其膝关节、踝关节、髋关节和趾关节等关节的发育极不完全或完全缺失
      • Development of soft tissues like cartilage, meniscus, ligaments are impaired by the lack of muscles force.
      • 软骨、半月板、韧带等软组织的发育，会因肌肉力量不足而受损
      • Altered synthesis of ECM molecules such as tenascin-C, PG and collagens and growth factor production in immobilized animals are responsible for the morphological abnormalities
      • 固定动物体内的肌腱蛋白 - C、蛋白聚糖（PG）、胶原蛋白等细胞外基质（ECM）分子合成发生改变，生长因子的产生也受影响，这些是导致形态异常的原因
      • 例 - 无骨骼肌的小鼠
        • Skeletal development of wild-type (left), and Myf52/2:MyoD2/2 (right), which has no skeletal muscle. Amyogenic无肌 mouse have fused and enlarged cervical vertebrae, abnormal curvature of the spine and abnormal formation of the sternum (arrow), mandible, palate, and clavicle.
        • Control (left) and muscleless mutant Myf5nlacZ/nlacZ:MyoD2/2 (right) forelimbs at TS23 Effects of absent musculature on forelimb development include incomplete bone formation in scapular blade (a), abnormal morphology of humeral ossification centers (b), and noncavitation of elbow joint (c)

          • 肩胛骨叶片骨形成不完全 (a)、肱骨骨化中心形态异常 (b) 及肘关节无腔化 (c)
        • Effect of abnormal muscle force on skeletogenesis in mouse models
          • Red indicates effect on rudiment or joint due to abnormal muscle, green indicates no effect, striped red and green indicates findings of affected and unaffected aspects

            • 红色表示异常肌肉对原基或关节产生的影响，绿色表示无影响，红绿色条纹表示存在受影响和未受影响的方面