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目录 contents

    摘要

    自噬是细胞重要的自我保护机制,多种伤害性刺激激活的自噬具有维持细胞稳态和正常功能的作用. 此外,自噬还参与调控恶性肿瘤、动脉粥样硬化等多种疾病的发生发展过程. 体内细胞处于复杂的力学微环境中,力学刺激参与调控细胞自噬,如压力可诱导心肌细胞的自噬、牵张力调控运动系统多种细胞的自噬、流体剪切力可激活血管内皮细胞和肿瘤细胞的自噬. 力学刺激诱导的细胞自噬依赖众多信号通路. 细胞骨架作为重要的调节因子,不仅参与细胞力学信号转导,同时可参与调控细胞自噬. 因此,细胞骨架与力学刺激诱导的细胞自噬密切相关. 本文结合最新的研究成果,综述力学刺激对细胞自噬的影响及其分子机制,以期为研究力学刺激对细胞生物学行为的影响提供新的视角,进而为相关疾病的治疗提供新思路和分子靶点.

    Abstract

    Autophagy is a significant protective mechanism of the body, which plays a key role in maintaining cell homeostasis and function during the process of coping with harmful stimuli. Additionally, autophagy also participates in regulating the occurrence and development of many diseases, such as malignant tumors and atherosclerosis. Cells are in a complex mechanical microenvironment and a variety of mechanical stimuli can induce autophagy. Stress can induce the autophagy of cardiomyocytes; tension regulates the autophagy of multiple cells in the motor system; and fluid shear stress activates the autophagy of vascular endothelial cells and tumor cells. The cell autophagy induced by mechanical stress relies on various signal pathways. The cytoskeleton, as an important regulatory factor, is not only involved in cell mechanotransduction, but also responsible for the specific process of autophagy. It is demonstrated that the cytoskeleton is closely related to autophagy induced by mechanical stress. In this paper, the effects of mechanical stimulation on autophagy and the underlying molecular mechanism are reviewed in combination with the recent research progress, which is expected to broaden a new prospective for studying the effects of mechanical stress on cell biological behavior and provide new strategies and molecular targets for the treatment of related diseases.

    自噬(autophagy)是细胞在饥饿、内质网应激、辐射、缺氧等应激原刺激下,转录表达自噬相关基因(autophagy related genes,Atg),并在胞质内形成自噬体,随后与溶酶体结合,降解回收胞内异常大分子化合物和受损细胞器的过程. 自噬在机体适应伤害性刺激,维持细胞正常功能和稳态中发挥重要作[1]. 自噬主要包括巨自噬(macroautophagy)、微自噬(microautophagy)、分子伴侣介导的自噬(chaperone-mediated autophagy,CMA)等三种类[2]. 本文主要讨论力学刺激诱导的细胞巨自噬及其分子机制.

    细胞的生化微环境对细胞的功能有重要影响,但细胞也处于复杂的力学微环境中. 力学刺激可影响细胞增殖、迁移、结构重建等一系列生物学过[3,4]. 近年来,细胞自噬作为机体的一种自我保护机制,在机体适应力学刺激过程中的作用受到广泛关注. 研究表明,自噬是细胞应对力学刺激的一个重要保护机[5]. 例如,血液流动产生的层流剪切力(laminar shear stress,LSS)可促进血管内皮细胞(vascular endothelial cells,VECs)自噬,对血管具有保护作[6]. 本文综述了近年来在该领域的研究成果,从自噬与细胞力学微环境、力学刺激对自噬的影响、细胞骨架与自噬等三方面阐述流体剪切力(fluid shear stress,FSS)等力学刺激对细胞自噬的调控作用及相应分子机制.

  • 1 自噬与细胞力学微环境

  • 1.1 自噬

    自噬是细胞内一种“自吞噬”现象,为真核生物高度保守的生物学过程. 自噬的主要功能是清除和降解胞内异常生物大分子和受损细胞器. 自噬过程中产生的降解产物可用于能量供应及细胞结构重建. 在生理状态下,细胞自噬水平较低,而在缺氧、内质网应激、饥饿等条件下,细胞自噬会被激活,进而维持细胞能量代谢平衡和正常的生理活动.

    自噬的过程是动态连续的,大致分为5个阶[7,8,9]. a.起始阶段:在各种诱导条件下,Atg1/unc-51样激酶1(unc-51 like kinase 1,ULK1)复合体去磷酸化,Atg1活性升高,进而促进下游自噬膜结构的出现;b.杯状分隔膜(isolation membrane)形成阶段:在自噬核心复合物的作用下,细胞浆、损坏的细胞器、错误折叠的蛋白质聚合体或入侵的病原体会被隔离膜包被,形成具有扁平杯状双层膜结构的自噬体前体;c.成熟自噬体(autophagosomes)形成阶段:在Atg蛋白的作用下,杯状双层膜结构不断延伸、扩展、封闭,并不断招募微管相关蛋白轻链3-Ⅱ(microtubule-associated protein light chain 3-Ⅱ,LC3-Ⅱ)分子,形成成熟自噬体;d.融合阶段:在细胞骨架的驱动下,自噬体外膜与溶酶体膜融合,自噬体内膜 及内容物进入溶酶体内,形成自噬溶酶体(autophagolysosomes);e.降解阶段:在溶酶体酶作用下,自噬体膜及内容物被降解,降解后的小分子化合物可供细胞再利用.

    自噬除了对机体有保护作用外,也参与多种病理过程. 细胞自噬异常与炎性肠病、神经退行性疾病、恶性肿瘤等多种疾病密切相[10,11,12]. 最新研究表明,自噬在恶性肿瘤中起“双刃剑”作用. 在肿瘤形成初期,自噬可通过维持细胞稳态抑制肿瘤发生发展;而在肿瘤形成后,自噬可帮助肿瘤细胞适应缺氧和营养缺乏的恶劣微环境,提高肿瘤细胞的生存、迁移与侵袭等能力,从而促进肿瘤的进[13,14]. 总之,自噬在不同来源的肿瘤组织中的作用不同,在同一肿瘤类型不同阶段中的作用效应也不尽相同.

  • 1.2 细胞力学微环境

    细胞微环境中存在各种形式的力学刺激,如牵张力(stretch stress)、流体静压力(hydrostatic pressure)及FSS[15,16]. 力学刺激作为一种重要的应激原,对细胞生物学行为的影响十分复[17]. 研究表明,生理水平的力学刺激是机体维持正常功能所必需的. 如在心脏发育过程中,力学刺激参与调控胚胎干细胞和心肌细胞的结构和功能,并参与调控胚胎干细胞向心肌细胞分[18]. 机体不仅在运动等正常活动中感受力学刺激,在心血管疾病、恶性肿瘤等病理条件下也会感受力学刺激. 本文以VECs和肿瘤细胞为例,介绍细胞的力学微环境.

    VECs不仅参与组成血管与组织间隙间的渗透屏障,还参与调控血管结构重建、生物活性物质的分泌和代谢、血管平滑肌细胞(vascular smooth muscle cells,VSMCs)的收缩等过[19,20]. 除了对生物化学刺激做出应答外,VECs还会直接接受机械应力的刺[21]. 血液流动会产生作用于血管壁的机械应力,包括周向牵张力、平行于血管壁的FSS及垂直于血管壁的压力. 周向牵张力因血压波动导致血管扩张而产生,FSS来源于流体相邻层间的流体黏度和流体速度梯[22]. 动脉血管网不同区域的结构差异决定了相应区域的不同机械应力作用模[23]. 在血管直线区域,FSS和牵张力的方向明确,VECs可通过负反馈调节机制降低血流和血压产生的机械应力对血管的影响,从而维持血管稳态. 而在血管分支点和弯曲区域,血流形式多样,单向FSS转变为震荡剪切应力(oscillatory shear stress,OSS),因此这些区域形成动脉粥样硬化(atherosclerosis,AS)斑块的风险较直线区域[24,25]. 综上,不同动脉区域的VECs会对机械应力产生不同的适应性反应. 在稳定的层流区域,VECs具有抗AS的特性,能够抑制血栓形成以及免疫细胞与血管壁的黏附;而在紊流区域,VECs的屏障功能、增殖能力均较弱,更易受到力学刺激的损伤.

    肿瘤微环境(tumor microenvironment,TME)是肿瘤细胞生存的特殊环境,由肿瘤周围的成纤维细胞、免疫细胞等多种细胞、细胞外基质(extracellular matrix,ECM)、血管淋巴管等组成,与肿瘤的发生发展及转移密切相[26]. 与正常组织相比,肿瘤细胞具有不断增殖的能力,并且肿瘤发生发展过程中往往伴随ECM的异常沉积以及血管增生. 因此,TME中的基质刚度、间质压、间隙流等均高于正常组[27,28]. TME中的各种力学刺激对肿瘤细胞的生物学行为具有重要的影响. 如乳腺肿瘤的基质刚度与肿瘤转移的风险呈负相关,基质刚度通过ULK1信号通路诱导上皮-间质转化(epithelial-mesenchymal transition,EMT)进而促进乳腺癌细胞的迁移侵[29],此外,FSS可促进卵巢癌细胞EMT和干细胞标志物的表达,并导致肿瘤细胞对顺铂和紫杉醇的耐[30]. 因此,肿瘤微环境中的力学刺激可通过影响肿瘤细胞的转移、EMT、干性、耐药性等调控恶性肿瘤的发生发展.

  • 2 力学刺激对自噬的影响

    机体细胞处于一个复杂的力学微环境中,异常的力学刺激与机体多种疾病的发生发展密切相关,如AS、心力衰竭等. 而在这些病理组织及细胞中通常能检测到自噬水平的异常. 因此,近年来越来越多的研究者关注异常力学刺激与细胞自噬的关系. 研究表明,自噬是细胞应对力学刺激的一种进化保守反应,允许细胞适应不断变化的物理微环境.

  • 2.1 力学刺激对心血管系统自噬的影响

    心血管系统的细胞时刻处于机械应力的刺激中. 其中,心肌细胞、VECs和VSMCs是主要的受力细胞. 心肌细胞主要感受压力和容量负荷引起的周向牵张力,VECs主要感受血液流动产生的FSS,而VSMCs主要感受来源于血压波动变化的周向牵张力. 研究表明,生理水平的机械应力参与调控心血管的发育、重塑、伤口愈合等过程,具有抗细胞凋亡、抗AS和抗血栓形成等作[18,31]. 而当上述机械应力出现异常,如血流压力或容量长期超负荷时,心血管系统细胞的稳态和功能会遭到破坏,出现血管炎症、心肌重构等病理现象,进而导致AS、心肌肥大、甚至是心衰等心血管疾病的发[32,33,34].

    自噬作为一种细胞死亡途径,在生理状态下能保证心血管系统的营养供应,对心血管系统细胞起保护作用. 但过度激活的自噬会导致细胞内必需大分子和细胞器的流失,进而引起细胞死亡,最终导致心肌肥大等心血管疾病的发[35]. 研究发现,心脏压力超负荷会通过促进Beclin1的表达、激活p38丝裂原活化蛋白激酶(p38 mitogen-activated protein kinases,p38 MAPK)等机制正向调控心肌细胞的自噬和病理性心脏重[36,37]. 而血浆中高密度脂蛋白(high density lipoprotein,HDL)作为心血管系统的保护因素,可激活PI3K/AKT信号通路以抑制压力超负荷诱导的心肌细胞自噬和心肌肥[38]. 有趣的是,除了压力超负荷会诱导心肌细胞自噬外,去应力负荷也可提高心肌细胞的自噬水平. 研究者利用小鼠心脏左心室去应力负荷模型发现,在去应力负荷条件下,心肌细胞中FoxO3表达水平和自噬水平显著升高,并出现进行性肌萎缩. 过表达FoxO3会显著激活心肌细胞的自[39]. 因此,自噬的激活在病理性机械应力引起的心肌肥大中起双重作用. 当应力超负荷时,自噬的激活会促进心肌肥大的发展;而当心脏的压力和容量负荷得到改善时,自噬的激活有利于心肌肥大的逆[40,41].

    VECs是心血管系统重要的组成成分,会感知多种力学刺激. 其中,FSS作为重要的血管活性因素,会影响VECs多种生理活动,如基因表达、增殖、迁移、形态发生[42]. 而自噬作为VECs应对应激原和维持细胞稳态的重要机制,也会受FSS的影响. FSS可通过激活VECs自噬调控一氧化氮(nitric oxide,NO)和内皮素1(endothelin-1, ET-1)的表达以维持VECs功能以及血管收缩性能. 同时,自噬还可能作为氧化剂-抗氧化剂平衡和炎症-抗炎平衡的关键调节因子,参与调控VECs对FSS的反[43,44]. 因此,VECs自噬的激活是FSS产生血管保护作用的重要机制. 但是,研究者发现不同大小及类型的FSS会对VECs的自噬产生不同的效应. 其中,LSS(12和20 dyn/cm2)会激活VECs自噬,而OSS(±5 dyn/cm2,1 Hz)和低幅度FSS (4 dyn/cm2)不会产生此效应. 并且,LSS诱导的自噬与经典的自噬相关通路无关,而是依赖于Sirt1蛋白. Sirt1通过感受LSS引起的细胞内活性氧自由基(reactive oxygen species,ROS)聚集激活细胞自噬,从而保护VECs[6]. 此外,LSS也可通过促进VECs中Rab4蛋白的表达激活自[45]. 然而,其他研究者通过体内外实验发现,OSS可通过激活细胞内氧化应激反应和c-Jun氨基末端激酶(c-Jun N-terminal kinase,JNK)信号通路诱导VECs发生自噬. 但与此同时,OSS也会损伤VECs的自噬流(autophagic flux)和线粒体DNA(mitochondrial DNA, mtDNA),从而导致VECs出现功能障碍,进而引发炎症反应和AS[46]. 另有研究报道,低FSS通过激活mTOR和抑制AMP依赖的蛋白激酶(adenosine 5'-monophosphate (AMP)-activated protein kinase,AMPK)信号通路降低VECs自噬水平,而高FSS会诱导VECs发生自[47]. 有趣的是,有研究指出,低水平FSS(3 dyn/cm2)也可促进VECs细胞的自噬,并且随着FSS的增加,自噬水平会逐渐降[48]. 综上,FSS对VECs自噬的影响并没有完全确定. 但目前研究表明,生理性LSS会诱导VECs发生自噬,对VECs具有保护作用,而非LSS或OSS会导致VECs自噬异常,进而影响其正常功能. 这与既往的结论相呼应:LSS可促进和维持VECs的存活和功能,具有预防AS的作用,而OSS会破坏VECs功能,促进AS的发[49,50].

  • 2.2 力学刺激对运动系统自噬的影响

    运动系统由骨、骨连接、骨骼肌三种器官组成,其能在保持机体稳定的同时实现准确、高效和多样化的活动. 力学刺激在运动系统的发育中起重要作用,正常的运动系统功能依赖于力学刺激对软骨形态发生、骨形态发生、关节形成及肌腱稳态和修复的调[51].

    软骨(cartilage)由软骨细胞(chondrocyte)、纤维、基质组成,在机体内起支持和保护作用. 软骨细胞作为一种机械敏感细胞,长期处于多种机械应力的刺激中,比如压力、牵张力、FSS[52,53]. 生理性力学刺激通过调节基质的合成维持软骨细胞的功能、稳态,而病理性力学刺激可通过直接损伤、诱导软骨细胞死亡及破坏ECM中蛋白多糖和胶原蛋白网络等作用使软骨发生退变,进而导致骨关节炎(osteoarthritis,OA)等疾病的发[54]. 自噬作为机体的一种应激反应机制,对于维持软骨的完整性和正常功能具有重要意义. 随着年龄的增长,软骨细胞自噬水平的下降会加剧OA的发[55]. 自噬水平的改变是软骨细胞对力学刺激做出的反应之一. 其中,自噬水平的变化趋势与力学刺激的作用时间密切相关. 短时程间歇循环牵张力(intermittent cyclic mechanical tension,ICMT)可激活终板软骨细胞的自噬;而长时程的ICMT会抑制软骨细胞的自噬,同时显著提高其钙化程度. 激活自噬会显著逆转ICMT引起的钙化程[56]. 上述结果表明,力学刺激作用于软骨后,细胞自噬水平的上调具有保护软骨的作用,一旦刺激时间过长,自噬水平逐渐下降,会导致病理状态,如钙化的发生. 此外,机械性损伤可通过抑制自噬的激活导致软骨细胞死亡,后者是OA发生的重要步[57]. 但是,有研究者在生物力学刺激诱导的大鼠颞下颌关节软骨退化模型中检测到自噬水平的升[58]. 这种结果差异可能是因为两者研究中所采用的力学刺激形式和取材部位不同. 综上,自噬在软骨细胞对力学刺激的应激反应中起保护作用,病理性力学刺激导致自噬水平异常是OA等疾病发生的重要机制.

    骨骼肌既是机体内储存蛋白质和能量的主要器官,也是机体产生力的主要器官. 其对力学刺激的适应性反应是维持自身结构、新陈代谢和功能所必需的. 力学刺激可激活骨骼肌纤维内多条Ca2+调节的信号通路,进而影响骨骼肌的生长发育. 已有研究报道,牵张力是骨骼肌纤维感受的主要力学刺激,其能促进蛋白质合成和肌肉生[59]. 此外,力学刺激也会导致骨骼肌细胞中错误折叠蛋白质水平的上升. 因此,自噬作为细胞的一种功能性降解途径,在骨骼肌对力学刺激的适应性反应中起重要调控作用,与骨骼肌的肥大和萎缩密切相关. 骨骼肌较高的基础自噬水平,不仅能通过降解错误折叠的蛋白质和损伤的细胞器为新的蛋白质合成提供原料,还能抑制细胞毒性聚集体的积累,进而降低骨骼肌细胞的应激反[60]. 研究表明,运动会导致小鼠骨骼肌纤维的自噬水平增加,后者在运动对机体产生有益代谢效应中起重要作[61]. 除小鼠之外,运动也能激活人骨骼肌的自噬. 分子伴侣介导的选择性自噬(chaperone-assisted selective autophagy,CASA)作为张力诱导的一种蛋白质平衡途径,在运动后的人骨骼肌中的活性显著增高. 并且,重复耐力运动会导致人骨骼肌的基础自噬水平升[62]. 这说明自噬在人骨骼肌适应力学刺激,维持自身结构中也起关键作用.

    骨为机体的其他部位提供结构支撑,具有保护其他组织器官、维持机体矿物质稳态和酸碱平衡等功能. 骨组织对力学刺激的适应反应依赖于成骨细胞(osteoblasts)、骨细胞(osteocytes)和破骨细胞(osteoclasts)的相互协作. 其中骨细胞占成年骨组织所有细胞的90%~95%,是骨组织中感受机械应力的主要细胞. 骨细胞通过自身复杂的通讯网络介导骨组织对机械应力的应答,并向成骨细胞和破骨细胞发送信号调节骨重塑过程. 最新研究表明,生理水平的机械应力会通过正向调控成骨细胞介导的骨形成和负向调控破骨细胞介导的骨吸收以增加骨质[63]. 但是,当力学刺激过强时,骨组织会产生较大的应变,导致骨骼产生微裂缝,甚至发生骨[64]. 自噬作为骨组织代谢和稳态的重要调节途径,参与调控骨吸收、骨形成等过程. 骨组织细胞自噬的异常与佩吉特骨病(Paget’s disease of bone,PDB)、骨质疏松(osteoporosis)等疾病的发生发展密切相关. 近年来,自噬在骨组织适应力学刺激中的作用受到越来越多的关注. 研究发现,对Wistar大鼠来源的成骨细胞样细胞施加循环牵张力(cyclic mechanical stretching,CMS)后,可检测到细胞中LC3B、Atg7等自噬相关蛋白质的表达水平升[65]. 此外,CMS可激活骨髓间充质干细胞(bone marrow mesenchymal stem cells,BMSCs)的自噬,后者在CMS促进BMSCs向成骨细胞分化中起关键作用. 激活自噬会促进BMSCs分化成骨细胞,改善小鼠后肢去负荷引起的骨丢[66]. 另有研究指出,FSS会诱导骨细胞发生自噬,FSS诱导的自噬与骨细胞的ATP代谢和生存能力密切相[67]. 综上,力学刺激可激活多种骨组织细胞的自噬,但具体分子机制仍待进一步的探究.

  • 2.3 力学刺激对恶性肿瘤自噬的影响

    肿瘤细胞处于一个复杂的物理微环境中,会受到各种机械应力的刺激. 其中,肿瘤细胞经常暴露于FSS为0.01~0.2 Pa(0.1~2.0 dyn/cm2)的间质流[68]. 自噬作为一把“双刃剑”,参与调控肿瘤的形成、增殖及转移等诸多方[13]. 此外,自噬在肿瘤细胞的力学信号转导中也起重要作用,多种力学刺激可激活肿瘤细胞的自噬.

    Lien[69]研究表明,LSS可激活多种肿瘤细胞系(肝癌Hep3B细胞、口腔鳞癌SCC25细胞、腺癌A549细胞和骨肉瘤MG63细胞)的自噬,而OSS不会诱导上述细胞发生自噬. 其中,LSS是通过骨形态发生蛋白受体IB(bone morphogenetic protein receptor IB,BMPRIB)介导的信号通路激活Hep3B细胞的自[69]. 这说明不同类型的FSS对肿瘤自噬有不同的效应. 进一步的研究表明,FSS可通过激活自噬促进肝癌HepG2和QGY-7703细胞的迁移能力;而抑制自噬会下调PI3K(phosphoinositide 3-kinase)、FAK(focal adhesion kinase)、Rho GTPases的表达水[70]. 此外,FSS也可激活宫颈癌HeLa细胞的自噬,且这个过程依赖于脂筏介导的力学信号转导通路以及p38 MAPK的激活. 破坏脂筏会抑制FSS诱导HeLa细胞发生自噬[71]. 除了FSS外,压力也可激活肿瘤细胞的自噬. 体外向乳腺癌MDA-MB-231细胞施加压力刺激时,也可观察到细胞内自噬体数量增[5]. 其他研究者还发现模拟微重力条件也可导致精原瘤TCam-2细胞的自噬水平出现上调. 因此,TME中多种力学刺激会诱导恶性肿瘤自噬的发生,后者在恶性肿瘤的生物学行为中起重要调控作用,但力学刺激调控肿瘤细胞自噬的具体机制尚不明确,仍待进一步的探究.

  • 3 细胞骨架与自噬

    细胞如何感知物理微环境中机械应力,进而做出相应响应一直是生物力学研究的一大热点. 研究表明,机械应力一方面可以直接激活细胞膜上相应的受体蛋白,如机械敏感型离子通道,进而触发细胞内化学信号通路,影响细胞的功能. 另一方面,机械应力可以通过整合素(integrin)-黏着斑(focal adhesion,FA)-细胞骨架(cytoskeleton)组成的应力传递桥梁到达胞质和胞核,从而调控细胞的生物学行[72]. 其中,细胞骨架由微管(microtubule,MT)、微丝(microfilament,MF)和中间纤维(intermediate filament,IF)组成,是细胞感受胞外应力作用并传递至胞内的力学信号转导过程中的重要枢纽,具有机械支持、维持细胞形态的作[73]. 机体内外部机械应力可引起细胞骨架的变构、重组,从而改变细胞局部的力学特征,进而影响细胞的形态、迁移及极性等一系列行[74]. 如FSS可引起VECs微丝细胞骨架的重构,进而导致VECs形态的改[75]. 机械应力诱导细胞骨架重构的过程受到多种分子的调控,如肌动蛋白相关蛋白2/3(actin related proteins 2/3,ARP2/3)复合体、丝切蛋白(cofilin)、Rho GTPases等. 其中,Rho GTPases是一类小分子G蛋白(small G protein),其在生物力学刺激下可通过多条途径调控MF的聚合和MT的组装,在力学信号转导通路中起重要作[72,76]. 目前诸多研究主要关注Cdc42、Rac1和RhoA等3个Rho GTPase家族成员在细胞骨架重构中的作用. 研究表明,RhoA主要调控肌动蛋白应力纤维和收缩环的形成,而Cdc42和Rac1参与板状伪足(lamellipodia)和丝状伪足(filopodia)的形[77].

    最新的研究表明,细胞骨架成分在特定的自噬过程中也起重要作用,其中酵母的自噬仅依赖于MF,而在哺乳动物细胞中,MF和MT均参与自[78]. MF是由肌动蛋白聚合形成的纤维丝,其在自噬过程中起重要作用. 在自噬起始阶段,肌动蛋白丝会参与维持欧米茄体(omegasome)的结构,后者是自噬体的前体之一;在杯状分隔膜形成阶段,分隔膜内穹顶部位的肌动蛋白网络支架可支撑分隔膜的延伸、扩展,从而促进自噬体的形成. 药物诱导肌动蛋白丝解聚会抑制自噬体的形成,并导致异常分隔膜的聚[79];在自噬体成熟和融合阶段,肌动蛋白丝在ARP2/3蛋白的调控下,会形成彗星拖尾一样的结构,进而推动自噬体向溶酶体的迁移,促进两者的融合. 抑制ARP2/3蛋白会导致细胞内成熟自噬体的数量减少,并抑制肌动蛋白彗星拖尾聚合物的形[80]. 已有研究报道,FSS可通过整合素-细胞骨架激活肝癌HepG2细胞的自噬,进而促进肝癌细胞的迁移侵袭. 化学抑制MF的聚合会显著降低HepG2细胞的自噬水平. 此外,FSS通过整合素调控MF细胞骨架重排的过程依赖于Rho GTPase家[81]. 上述结果表明,当细胞自噬水平升高时,MF细胞骨架作为自噬发生发展的动力基础,参与调控自噬的多个阶段,并且其功能可能受到Rho GTPase家族不同成员的严格调节. MT在自噬中的作用一直受到广泛关注,其不仅能促进自噬体的形成,还可加速自噬体与溶酶体的融[82]. 随机分布于细胞质中的自噬体会以MT为转运“轨道”,到达微管组织中心(microtubule organizing center,MTOC),从而与集中分布于MTOC核周的溶酶体融合. 并且,自噬体沿着MT的双向运动过程依赖于动力蛋白分子马[83]. 研究表明,药物诱导MT解聚会显著抑制饥饿诱导的自噬体形成,并阻碍自噬流的发生. 此外,具有稳定微管结构,抑制微管动态变化作用的紫杉醇也可抑制自噬体的形[84]. 所以,MT的正常动态变化在自噬体形成和自噬体转运过程中起重要作用,可促进自噬体与溶酶体的融合.

    综上,细胞骨架不仅参与细胞内外力学信号的转导,还与自噬的进程密切相关,这提示细胞骨架成分可能是力学刺激诱导自噬过程中的重要中间调节因子. 但目前直接表明细胞物理微环境中的各种力学刺激可通过细胞骨架调控自噬的研究不多,因此细胞骨架系统各成分在力学刺激诱导自噬发生发展的各个阶段中的具体作用及机制仍待进一步的探索和研究.

  • 4 讨论及展望

    力学刺激作为一种常见的应激原,与机体多种病理生理过程密切相关. 生理水平的力学刺激对维持细胞的稳态和正常生理功能有重要作用. 但当力学刺激出现异常时,机体细胞会适应不良,进而导致相应的组织器官出现障碍. 如压力超负荷导致心肌肥大、OSS诱导血管发生炎症反应和AS等. 细胞内力学反馈控制系统和力学信号传导通路在感知、传递力学信号、调节细胞功能中起重要作用. 而自噬作为机体细胞在应激条件下的一种重要保护性机制,在机体适应力学刺激的过程中起重要作用(图1).

    图1
                            力学刺激通过自噬调节细胞功能

    图1 力学刺激通过自噬调节细胞功能

    Fig. 1 Mechanical stimuli mediated cell function via autophagy activation

    近年来,越来越多的研究表明,力学刺激与细胞自噬密切相关. 多种机械应力可激活细胞自噬,但其具体机制仍待进一步的探究. 细胞骨架是细胞内参与力学信号转导的重要结构. 研究表明,其组成成分MT、MF等在自噬特定过程中也起调控作用,这表明细胞骨架有可能是力学刺激与自噬之间的重要桥梁. 因此进一步研究在生理和病理状态下,细胞骨架各成分在力学刺激诱导细胞自噬中的作用及具体机制,有助于了解自噬相关疾病发生发展的本质,并有助于发展新的疾病治疗策略. 本课题组未来将深入探索细胞骨架系统在FSS诱导细胞发生自噬过程中的作用. 重点关注细胞骨架调控因子RhoA在FSS诱导肝癌细胞自噬中的调控作用及相应的力学信号传导通路.

    Tel: 86-28-85402314, Email: liuxiaohg@scu.edu.cn

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周芳

机 构:四川大学华西基础医学与法医学院生物医学工程研究室,成都 610041

Affiliation:Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China

闫志平

机 构:四川大学华西基础医学与法医学院生物医学工程研究室,成都 610041

Affiliation:Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China

马伦杰

机 构:四川大学华西基础医学与法医学院生物医学工程研究室,成都 610041

Affiliation:Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China

刘肖珩

机 构:四川大学华西基础医学与法医学院生物医学工程研究室,成都 610041

Affiliation:Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China

角 色:通讯作者

Role:Corresponding author

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图1 力学刺激通过自噬调节细胞功能

Fig. 1 Mechanical stimuli mediated cell function via autophagy activation

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