细胞外基质硬度和厚度对细胞生长的影响
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摘要
背景:细胞外基质的力学性质会影响细胞的铺展、增殖和分化,对于组织工程和再生医学研究及应用均有极其重要的意义。目的:总结近年来有关基质力学性质对细胞生长的影响,并分析基质厚度和硬度之间是否存在关系,为体外构建功能性组织提供实验方法参考。方法:作者检索1988至2016年百链云数据库和PubMed数据库,选择与基质力学性质对细胞生长影响有关的文献,进行系统整理、总结归纳和分析。结果与结论:检索到文章254篇,最终纳入43篇。通过总结及分析发现黏附在基质上的细胞结构和功能与其所处的外环境有很大的关系。体外模拟实验表明基质硬度的增大会使得细胞的形态发生变化,铺展面积增大,增殖水平提高,同样也会对细胞的分化有影响。当基质厚度在一定范围内时,细胞可以感知到基质厚度的变化。当基质厚度超过一定范围,细胞则感知不到基质的厚度,影响细胞的主要是基质的硬度及其交联程度,此厚度范围从几微米到60μm不等,与接种细胞的水平尺寸有关。
BACKGROUND: The mechanical properties of extracellular matrix can affect cell spreading, proliferation and differentiation. It is of extremely vital significance for tissue engineering and regenerative medicine. OBJECTIVE: To summarize the progress of matrix mechanical properties influences on cell growth and to analyze if there is a relationship between matrix thickness and stiffness, in order to provide experimental methods for functional tissue construction in vitro.METHODS: The author performed a data retrieval of Pub Med and Bailianyun databases from 1988 to 2016 to search the articles addressing the influence of extracellular matrix mechanical properties on cell growth, and systematically reviewed the literatures. RESULTS AND CONCLUSION: A total of 254 references were retrieved, and 43 articles were finally involved in the result analysis according to the inclusion and exclusion criteria. After summarizing and analyzing, it is found that the structure and function of cells adhering to the matrix are related to the extracellular environment. In vitro simulation experiments have shown that the increasing of matrix stiffness can change the cell morphology, increase the spreading area and proliferation rate, and can also influence the cell differentiation. When the matrix thickness is in a certain range, cells can sense the change of matrix thickness. When the matrix thickness is out of range, cells cannot perceive the matrix thickness. Matrix stiffness and cross-linking degree have certain effects on the cells, and the matrix thickness ranges from several microns to 60 microns, which is associated with the horizontal size of seeded cells.
BACKGROUND: The mechanical properties of extracellular matrix can affect cell spreading, proliferation and differentiation. It is of extremely vital significance for tissue engineering and regenerative medicine. OBJECTIVE: To summarize the progress of matrix mechanical properties influences on cell growth and to analyze if there is a relationship between matrix thickness and stiffness, in order to provide experimental methods for functional tissue construction in vitro.METHODS: The author performed a data retrieval of Pub Med and Bailianyun databases from 1988 to 2016 to search the articles addressing the influence of extracellular matrix mechanical properties on cell growth, and systematically reviewed the literatures. RESULTS AND CONCLUSION: A total of 254 references were retrieved, and 43 articles were finally involved in the result analysis according to the inclusion and exclusion criteria. After summarizing and analyzing, it is found that the structure and function of cells adhering to the matrix are related to the extracellular environment. In vitro simulation experiments have shown that the increasing of matrix stiffness can change the cell morphology, increase the spreading area and proliferation rate, and can also influence the cell differentiation. When the matrix thickness is in a certain range, cells can sense the change of matrix thickness. When the matrix thickness is out of range, cells cannot perceive the matrix thickness. Matrix stiffness and cross-linking degree have certain effects on the cells, and the matrix thickness ranges from several microns to 60 microns, which is associated with the horizontal size of seeded cells.
引文
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[2]Boontheekul T,Hill EE,Kong HJ,et al.Regulating myoblast phenotype through controlled gel stiffness and degradation.Tissue Eng.2007;13(7):1431-1442.
[3]Pelham RJ Jr,Wang Y.Cell locomotion and focal adhesions are regulated by substrate flexibility.Proc Natl Acad Sci U S A.1997;94(25):13661-13665.
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[10]Palchesko RN,Zhang L,Sun Y,et al.Development of polydimethylsiloxane substrates with tunable elastic modulus to study cell mechanobiology in muscle and nerve.PLo S One.2012;7(12):e51499.
[11]Sazonova OV,Isenberg BC,Herrmann J,et al.Extracellular matrix presentation modulates vascular smooth muscle cell mechanotransduction.Matrix Biol.2015;41:36-43.
[12]Bonewald LF.The amazing osteocyte.J Bone Miner Res.2011;26(2):229-238.
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[17]Simon DN,Wilson KL.The nucleoskeleton as a genome-associated dynamic'network of networks'.Nat Rev Mol Cell Biol.2011;12(11):695-708.
[18]Yip AK,Iwasaki K,Ursekar C,et al.Cellular response to substrate rigidity is governed by either stress or strain.Biophys J.2013;104(1):19-29.
[19]刘蕾,谈雯雯,杨团民,等.细胞外基质硬度对成骨细胞MC3T3-E1形态、增殖及矿化能力的影响[J].陕西医学杂志,2015,44(10):1300-1303.
[20]杨本艳姿,王红兵,谭乔燕,等.不同基底硬度对人肝癌细胞黏附、铺展和迁移的影响[J].医用生物力学,2012,27(3):305-311.
[21]陈莉,李长樱,杨新华,等.基质硬度对乳腺癌MDA-MB-231细胞增殖能力的影响[J].中华乳腺病杂志:电子版,2008,2(2):184-189.
[22]王阿娴,唐丽,梁源,等.人骨髓来源细胞外基质对人牙周膜干细胞增殖的影响[J].中国组织工程研究,2014,18(6):938-943.
[23]Friedman SL,Roll FJ,Boyles J,et al.Maintenance of differentiated phenotype of cultured rat hepatic lipocytes by basement membrane matrix.J Biol Chem.1989;264(18):10756-10762.
[24]Sohara N,Znoyko I,Levy MT,et al.Reversal of activation of human myofibroblast-like cells by culture on a basement membrane-like substrate.J Hepatol.2002;37(2):214-221.
[25]Yeung T,Georges PC,Flanagan LA,et al.Effects of substrate stiffness on cell morphology,cytoskeletal structure,and adhesion.Cell Motil Cytoskeleton.2005;60(1):24-34.
[26]Discher DE,Janmey P,Wang YL.Tissue cells feel and respond to the stiffness of their substrate.Science.2005;310(5751):1139-1143.
[27]Engler AJ,Sen S,Sweeney HL,et al.Matrix elasticity directs stem cell lineage specification.Cell.2006;126(4):677-689.
[28]Evans ND,Minelli C,Gentleman E,et al.Substrate stiffness affects early differentiation events in embryonic stem cells.Eur Cell Mater.2009;18:1-14.
[29]Das M,Sundell IB,Koka PS.Adult mesenchymal stem cells and their potency in the cell-based therapy.J Stem Cells.2013;8(1):1-16.
[30]Eirin A,Lerman LO.Mesenchymal stem cell treatment for chronic renal failure.Stem Cell Res Ther.2014;5(4):83.
[31]Zeng X,Couture LA.Pluripotent stem cells for Parkinson's disease:progress and challenges.Stem Cell Res Ther.2013;4(2):25.
[32]Engler AJ,Sen S,Sweeney HL,et al.Matrix elasticity directs stem cell lineage specification.Cell.2006;126(4):677-689.
[33]Zoldan J,Karagiannis ED,Lee CY,et al.The influence of scaffold elasticity on germ layer specification of human embryonic stem cells.Biomaterials.2011;32(36):9612-9621.
[34]Gilbert PM,Havenstrite KL,Magnusson KE,et al.Substrate elasticity regulates skeletal muscle stem cell self-renewal in culture.Science.2010;329(5995):1078-1081.
[35]Tse JR,Engler AJ.Stiffness gradients mimicking in vivo tissue variation regulate mesenchymal stem cell fate.PLo S One.2011;6(1):e15978.
[36]Winer JP,Janmey PA,Mc Cormick ME,et al.Bone marrow-derived human mesenchymal stem cells become quiescent on soft substrates but remain responsive to chemical or mechanical stimuli.Tissue Eng Part A.2009;15(1):147-154.
[37]Levy-Mishali M,Zoldan J,Levenberg S.Effect of scaffold stiffness on myoblast differentiation.Tissue Eng Part A.2009;15(4):935-944.
[38]Engler AJ,Griffin MA,Sen S,et al.Myotubes differentiate optimally on substrates with tissue-like stiffness:pathological implications for soft or stiff microenvironments.J Cell Biol.2004;166(6):877-887.
[39]Boontheekul T,Hill EE,Kong HJ,et al.Regulating myoblast phenotype through controlled gel stiffness and degradation.Tissue Eng.2007;13(7):1431-1442.
[40]Lin YC,Tambe DT,Park CY,et al.Mechanosensing of substrate thickness.Phys Rev E Stat Nonlin Soft Matter Phys.2010;82(4 Pt 1):041918.
[41]Mullen CA,Vaughan TJ,Billiar KL,et al.The effect of substrate stiffness,thickness,and cross-linking density on osteogenic cell behavior.Biophys J.2015;108(7):1604-1612.
[42]Wan LQ,Ronaldson K,Park M,et al.Micropatterned mammalian cells exhibit phenotype-specific left-right asymmetry.Proc Natl Acad Sci U S A.2011;108(30):12295-12300.
[43]Gribova V,Gauthier-Rouvière C,Albigès-Rizo C,et al.Effect of RGD functionalization and stiffness modulation of polyelectrolyte multilayer films on muscle cell differentiation.Acta Biomater.2013;9(5):6468-6480.
[2]Boontheekul T,Hill EE,Kong HJ,et al.Regulating myoblast phenotype through controlled gel stiffness and degradation.Tissue Eng.2007;13(7):1431-1442.
[3]Pelham RJ Jr,Wang Y.Cell locomotion and focal adhesions are regulated by substrate flexibility.Proc Natl Acad Sci U S A.1997;94(25):13661-13665.
[4]Discher DE,Janmey P,Wang YL.Tissue cells feel and respond to the stiffness of their substrate.Science.2005;310(5751):1139-1143.
[5]Engler AJ,Griffin MA,Sen S,et al.Myotubes differentiate optimally on substrates with tissue-like stiffness:pathological implications for soft or stiff microenvironments.J Cell Biol.2004;166(6):877-887.
[6]Lin YC,Tambe DT,Park CY,et al.Mechanosensing of substrate thickness.Phys Rev E Stat Nonlin Soft Matter Phys.2010;82(4 Pt 1):041918.
[7]Butler JP,Toli?-N?rrelykke IM,Fabry B,et al.Traction fields,moments,and strain energy that cells exert on their surroundings.Am J Physiol Cell Physiol.2002;282(3):C595-605.
[8]Lv H,Li L,Sun M,et al.Mechanism of regulation of stem cell differentiation by matrix stiffness.Stem Cell Res Ther.2015;6:103.
[9]Mullen CA,Haugh MG,Schaffler MB,et al.Osteocyte differentiation is regulated by extracellular matrix stiffness and intercellular separation.J Mech Behav Biomed Mater.2013;28:183-194.
[10]Palchesko RN,Zhang L,Sun Y,et al.Development of polydimethylsiloxane substrates with tunable elastic modulus to study cell mechanobiology in muscle and nerve.PLo S One.2012;7(12):e51499.
[11]Sazonova OV,Isenberg BC,Herrmann J,et al.Extracellular matrix presentation modulates vascular smooth muscle cell mechanotransduction.Matrix Biol.2015;41:36-43.
[12]Bonewald LF.The amazing osteocyte.J Bone Miner Res.2011;26(2):229-238.
[13]Papachroni KK,Karatzas DN,Papavassiliou KA,et al.Mechanotransduction in osteoblast regulation and bone disease.Trends Mol Med.2009;15(5):208-216.
[14]Santos A,Bakker AD,Klein-Nulend J.The role of osteocytes in bone mechanotransduction.Osteoporos Int.2009;20(6):1027-1031.
[15]王红兵,林雨,杨力,等.基质硬度和表面形貌对细胞生物学行为的影响[J].细胞生物学杂志,2009,31(5):608-614.
[16]De R,Zemel A,Safran SA.Do cells sense stress or strain?Measurement of cellular orientation can provide a clue.Biophys J.2008;94(5):L29-31.
[17]Simon DN,Wilson KL.The nucleoskeleton as a genome-associated dynamic'network of networks'.Nat Rev Mol Cell Biol.2011;12(11):695-708.
[18]Yip AK,Iwasaki K,Ursekar C,et al.Cellular response to substrate rigidity is governed by either stress or strain.Biophys J.2013;104(1):19-29.
[19]刘蕾,谈雯雯,杨团民,等.细胞外基质硬度对成骨细胞MC3T3-E1形态、增殖及矿化能力的影响[J].陕西医学杂志,2015,44(10):1300-1303.
[20]杨本艳姿,王红兵,谭乔燕,等.不同基底硬度对人肝癌细胞黏附、铺展和迁移的影响[J].医用生物力学,2012,27(3):305-311.
[21]陈莉,李长樱,杨新华,等.基质硬度对乳腺癌MDA-MB-231细胞增殖能力的影响[J].中华乳腺病杂志:电子版,2008,2(2):184-189.
[22]王阿娴,唐丽,梁源,等.人骨髓来源细胞外基质对人牙周膜干细胞增殖的影响[J].中国组织工程研究,2014,18(6):938-943.
[23]Friedman SL,Roll FJ,Boyles J,et al.Maintenance of differentiated phenotype of cultured rat hepatic lipocytes by basement membrane matrix.J Biol Chem.1989;264(18):10756-10762.
[24]Sohara N,Znoyko I,Levy MT,et al.Reversal of activation of human myofibroblast-like cells by culture on a basement membrane-like substrate.J Hepatol.2002;37(2):214-221.
[25]Yeung T,Georges PC,Flanagan LA,et al.Effects of substrate stiffness on cell morphology,cytoskeletal structure,and adhesion.Cell Motil Cytoskeleton.2005;60(1):24-34.
[26]Discher DE,Janmey P,Wang YL.Tissue cells feel and respond to the stiffness of their substrate.Science.2005;310(5751):1139-1143.
[27]Engler AJ,Sen S,Sweeney HL,et al.Matrix elasticity directs stem cell lineage specification.Cell.2006;126(4):677-689.
[28]Evans ND,Minelli C,Gentleman E,et al.Substrate stiffness affects early differentiation events in embryonic stem cells.Eur Cell Mater.2009;18:1-14.
[29]Das M,Sundell IB,Koka PS.Adult mesenchymal stem cells and their potency in the cell-based therapy.J Stem Cells.2013;8(1):1-16.
[30]Eirin A,Lerman LO.Mesenchymal stem cell treatment for chronic renal failure.Stem Cell Res Ther.2014;5(4):83.
[31]Zeng X,Couture LA.Pluripotent stem cells for Parkinson's disease:progress and challenges.Stem Cell Res Ther.2013;4(2):25.
[32]Engler AJ,Sen S,Sweeney HL,et al.Matrix elasticity directs stem cell lineage specification.Cell.2006;126(4):677-689.
[33]Zoldan J,Karagiannis ED,Lee CY,et al.The influence of scaffold elasticity on germ layer specification of human embryonic stem cells.Biomaterials.2011;32(36):9612-9621.
[34]Gilbert PM,Havenstrite KL,Magnusson KE,et al.Substrate elasticity regulates skeletal muscle stem cell self-renewal in culture.Science.2010;329(5995):1078-1081.
[35]Tse JR,Engler AJ.Stiffness gradients mimicking in vivo tissue variation regulate mesenchymal stem cell fate.PLo S One.2011;6(1):e15978.
[36]Winer JP,Janmey PA,Mc Cormick ME,et al.Bone marrow-derived human mesenchymal stem cells become quiescent on soft substrates but remain responsive to chemical or mechanical stimuli.Tissue Eng Part A.2009;15(1):147-154.
[37]Levy-Mishali M,Zoldan J,Levenberg S.Effect of scaffold stiffness on myoblast differentiation.Tissue Eng Part A.2009;15(4):935-944.
[38]Engler AJ,Griffin MA,Sen S,et al.Myotubes differentiate optimally on substrates with tissue-like stiffness:pathological implications for soft or stiff microenvironments.J Cell Biol.2004;166(6):877-887.
[39]Boontheekul T,Hill EE,Kong HJ,et al.Regulating myoblast phenotype through controlled gel stiffness and degradation.Tissue Eng.2007;13(7):1431-1442.
[40]Lin YC,Tambe DT,Park CY,et al.Mechanosensing of substrate thickness.Phys Rev E Stat Nonlin Soft Matter Phys.2010;82(4 Pt 1):041918.
[41]Mullen CA,Vaughan TJ,Billiar KL,et al.The effect of substrate stiffness,thickness,and cross-linking density on osteogenic cell behavior.Biophys J.2015;108(7):1604-1612.
[42]Wan LQ,Ronaldson K,Park M,et al.Micropatterned mammalian cells exhibit phenotype-specific left-right asymmetry.Proc Natl Acad Sci U S A.2011;108(30):12295-12300.
[43]Gribova V,Gauthier-Rouvière C,Albigès-Rizo C,et al.Effect of RGD functionalization and stiffness modulation of polyelectrolyte multilayer films on muscle cell differentiation.Acta Biomater.2013;9(5):6468-6480.