支架机械特征介导Yes相关蛋白信号调节干细胞生物行为的研究进展

doi:10.3877/cma.j.issn.1674-1366.2022.06.004

干细胞可感知局部微环境理化特征，传递并转导机械或化学信号以调控黏附、增殖、分化、代谢和免疫等生物行为。组织工程常通过设计人工支架模拟体内微环境机械特征对干细胞进行仿生调控，研究发现从细胞感知外界机械刺激到启动生物行为发生变化的过程中，Yes相关蛋白（YAP）发挥了重要作用。本文旨在对支架机械特征的功能，及其介导YAP调控干细胞生物行为作用机制的研究进展进行综述。

关键词: Yes相关蛋白, 干细胞, 支架, 机械特征, 生物行为

Stem cells can sense the physical or chemical signals of the local microenvironment to regulate biological behaviors including adhesion, proliferation, differentiation, metabolism, and immunity. A common strategy of designing artificial scaffolds in tissue engineering is to simulate the mechanical properties of the microenvironment in vivo. Growing evidence suggests that Yes-associated protein (YAP) plays an important role in the process by which stem cells recognize external mechanical cues and transform the information into cellular responses. In this review, we summarized the research progress on the mechanical properties of scaffolds and the mechanism of YAP in regulating stem cell biological behavior.

Key words: Yes-associated protein, Stem cells, Scaffold, Mechanical properties, Biological behavior

图1 Yes相关蛋白（YAP）参与机械信号传导的信号通路模式图　Integrins：整合素受体；Talin：踝蛋白；Vinculin：黏着斑蛋白；Src：肉瘤基因；FAK：黏着斑激酶；F-actin：F-肌动蛋白；RhoA：RAS同源基因家族成员A；ROCK：Rho激酶；LATS1/2：大肿瘤抑制因子1/2；TAZ：Tafazzin蛋白；TEAD：转录因子TEAD。

[1]	Kfoury Y，Scadden DT. Mesenchymal cell contributions to the stem cell niche[J]. Cell Stem Cell，2015，16(3):239-253. DOI：10.1016/j.stem.2015.02.019.
[2]	Guilak F，Cohen DM，Estes BT，et al. Control of stem cell fate by physical interactions with the extracellular matrix[J]. Cell Stem Cell，2009，5(1):17-26. DOI：10.1016/j.stem.2009.06.016.
[3]	Cunniffe GM，Díaz-Payno PJ，Sheehy EJ，et al. Tissue-specific extracellular matrix scaffolds for the regeneration of spatially complex musculoskeletal tissues[J]. Biomaterials，2019，188:63-73. DOI：10.1016/j.biomaterials.2018.09.044.
[4]	Mertz AF，Che Y，Banerjee S，et al. Cadherin-based intercellular adhesions organize epithelial cell-matrix traction forces[J]. Proc Natl Acad Sci U S A，2013，110(3):842-847. DOI：10.1073/pnas.1217279110.
[5]	Huang G，Greenspan DS. ECM roles in the function of metabolic tissues[J]. Trends Endocrinol Metab，2012，23(1):16-22. DOI：10.1016/j.tem.2011.09.006.
[6]	Elosegui-Artola A，Bazellières E，Allen MD，et al. Rigidity sensing and adaptation through regulation of integrin types[J]. Nat Mater，2014，13(6):631-637. DOI：10.1038/nmat3960.
[7]	Urbanczyk M，Layland SL，Schenke-Layland K. The role of extracellular matrix in biomechanics and its impact on bioengineering of cells and 3D tissues[J]. Matrix Biol，2020，85/86:1-14. DOI：10.1016/j.matbio.2019.11.005.
[8]	Chakraborty S，Njah K，Pobbati AV，et al. Agrin as a mechanotransduction signal regulating yap through the hippo pathway[J]. Cell Rep，2017，18(10):2464-2479. DOI：10.1016/j.celrep.2017.02.041.
[9]	Seo J，Kim J. Regulation of Hippo signaling by actin remodeling[J]. BMB Rep，2018，51(3):151-156. DOI：10.5483/bmbrep.2018.51.3.012.
[10]	Aragona M，Panciera T，Manfrin A，et al. A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors[J]. Cell，2013，154(5):1047-1059. DOI：10.1016/j.cell.2013.07.042.
[11]	Dupont S，Morsut L，Aragona M，et al. Role of YAP/TAZ in mechanotransduction[J]. Nature，2011，474(7350):179-183. DOI：10.1038/nature10137.
[12]	Gouveia RM，Vajda F，Wibowo JA，et al. YAP，ΔNp63，and β-catenin signaling pathways are involved in the modulation of corneal epithelial stem cell phenotype induced by substrate stiffness[J]. Cells，2019，8(4):347. DOI：10.3390/cells8040347.
[13]	Swanson WB，Omi M，Woodbury SM，et al. Scaffold pore curvature influences ΜSC fate through differential cellular organization and YAP/TAZ activity[J]. Int J Mol Sci，2022，23(9):4499. DOI：10.3390/ijms23094499.
[14]	Chen Z，Bachhuka A，Wei F，et al. Nanotopography-based strategy for the precise manipulation of osteoimmunomodulation in bone regeneration[J]. Nanoscale，2017，9(46):18129-18152. DOI：10.1039/c7nr05913b.
[15]	Ma J，Li J，Hu S，et al. Collagen modified anisotropic PLA scaffold as a base for peripheral nerve regeneration[J]. Macromol Biosci，2022，22(7):e2200119. DOI：10.1002/mabi.202200119.
[16]	Wan S，Fu X，Ji Y，et al. FAK- and YAP/TAZ dependent mechanotransduction pathways are required for enhanced immunomodulatory properties of adipose-derived mesenchymal stem cells induced by aligned fibrous scaffolds[J]. Biomaterials，2018，171:107-117. DOI：10.1016/j.biomaterials.2018.04.035.
[17]	Tang H，Yi B，Wang X，et al. Understanding the cellular responses based on low-density electrospun fiber networks[J]. Mater Sci Eng C Mater Biol Appl，2021，119:111470. DOI：10.1016/j.msec.2020.111470.
[18]	Shi W，Zhang X，Bian L，et al. Alendronate crosslinked chitosan/polycaprolactone scaffold for bone defects repairing[J]. Int J Biol Macromol，2022，204:441-456. DOI：10.1016/j.ijbiomac.2022.02.007.
[19]	Lin Z，Zhao C，Lei Z，et al. Epidermal stem cells maintain stemness via a biomimetic micro/nanofiber scaffold that promotes wound healing by activating the Notch signaling pathway[J]. Stem Cell Res Ther，2021，12(1):341. DOI：10.1186/s13287-021-02418-2.
[20]	Das A，Adhikary S，Chowdhury AR，et al. Leveraging substrate stiffness to promote stem cell asymmetric division via mechanotransduction-polarity protein axis and its bayesian regression analysis[J]. Rejuvenation Res，2022，25(2):59-69. DOI：10.1089/rej.2021.0039.
[21]	Rezaei H，Rezaie Z，Seifati SM，et al. Poly-phosphate increases SMC differentiation of mesenchymal stem cells on PLGA-polyurethane nanofibrous scaffold[J]. Cell Tissue Bank，2020，21(3):495-505. DOI：10.1007/s10561-020-09836-1.
[22]	Song JE，Tripathy N，Cha SR，et al. Three-dimensional duck′s feet collagen/PLGA scaffold for chondrification：Role of pore size and porosity[J]. J Biomater Sci Polym Ed，2018，29(7/9):932-941. DOI：10.1080/09205063.2017.1394712.
[23]	Gangolli RA，Devlin SM，Gerstenhaber JA，et al. A bilayered poly（lactic-co-glycolic acid）scaffold provides differential cues for the differentiation of dental pulp stem cells[J]. Tissue Eng Part A，2019，25(3/4):224-233. DOI：10.1089/ten.TEA.2018.0041.
[24]	Shafiee A，Kehtari M，Zarei Z，et al. An in situ hydrogel-forming scaffold loaded by PLGA microspheres containing carbon nanotube as a suitable niche for neural differentiation[J]. Mater Sci Eng C Mater Biol Appl，2021，120:111739. DOI：10.1016/j.msec.2020.111739.
[25]	Yang L，Ge L，van Rijn P. Synergistic effect of cell-derived extracellular matrices and topography on osteogenesis of mesenchymal stem cells[J]. ACS Appl Mater Interfaces，2020，12(23):25591-25603. DOI：10.1021/acsami.0c05012.
[26]	Hu J，Wang Z，Miszuk JM，et al. Vanillin-bioglass cross-linked 3D porous chitosan scaffolds with strong osteopromotive and antibacterial abilities for bone tissue engineering[J]. Carbohydr Polym，2021，271:118440. DOI：10.1016/j.carbpol.2021.118440.
[27]	Zhang W，Chu G，Wang H，et al. Effects of matrix stiffness on the differentiation of multipotent stem cells[J]. Curr Stem Cell Res Ther，2020，15(5):449-461. DOI：10.2174/1574888x15666200408114632.
[28]	Mousavi SJ，Doweidar MH. Role of mechanical cues in cell differentiation and proliferation：A 3D numerical model[J]. PLoS One，2015，10(5):e0124529. DOI：10.1371/journal.pone.0124529.
[29]	Huebsch N，Arany PR，Mao AS，et al. Harnessing traction-mediated manipulation of the cell/matrix interface to control stem-cell fate[J]. Nat Mater，2010，9(6):518-526. DOI：10.1038/nmat2732.
[30]	Liu N，Zhou M，Zhang Q，et al. Effect of substrate stiffness on proliferation and differentiation of periodontal ligament stem cells[J]. Cell Prolif，2018，51(5):e12478. DOI：10.1111/cpr.12478.
[31]	Meng J，Boschetto F，Yagi S，et al. Enhancing the bioactivity of melt electrowritten PLLA scaffold by convenient，green，and effective hydrophilic surface modification[J]. Mater Sci Eng C Mater Biol Appl，2022，135:112686. DOI：10.1016/j.msec.2022.112686.
[32]	Xu X，Zhou Y，Zheng K，et al. 3D polycaprolactone/gelatin-oriented electrospun scaffolds promote periodontal regeneration[J]. ACS Appl Mater Interfaces，2022，14(41):46145-46160. DOI：10.1021/acsami.2c03705.
[33]	Chen S，Guo Y，Liu R，et al. Tuning surface properties of bone biomaterials to manipulate osteoblastic cell adhesion and the signaling pathways for the enhancement of early osseointegration[J]. Colloids Surf B Biointerfaces，2018，164:58-69. DOI：10.1016/j.colsurfb.2018.01.022.
[34]	Dabrowski B，Swieszkowski W，Godlinski D，et al. Highly porous titanium scaffolds for orthopaedic applications[J]. J Biomed Mater Res B Appl Biomater，2010，95(1):53-61. DOI：10.1002/jbm.b.31682.
[35]	Lian M，Sun B，Han Y，et al. A low-temperature-printed hierarchical porous sponge-like scaffold that promotes cell-material interaction and modulates paracrine activity of MSCs for vascularized bone regeneration[J]. Biomaterials，2021，274:120841. DOI：10.1016/j.biomaterials.2021.120841.
[36]	Khlusov IA，Dekhtyar Y，Sharkeev YP，et al. Nanoscale electrical potential and roughness of a calcium phosphate surface promotes the osteogenic phenotype of stromal cells[J]. Materials （Basel），2018，11(6):978. DOI：10.3390/ma11060978.
[37]	Chu G，Yuan Z，Zhu C，et al. Substrate stiffness- and topography-dependent differentiation of annulus fibrosus-derived stem cells is regulated by Yes-associated protein[J]. Acta Biomater，2019，92:254-264. DOI：10.1016/j.actbio.2019.05.013.
[38]	Liu Y，Li X，Jiang C，et al. Clinical applications of concentrated growth factors membrane for sealing the socket in alveolar ridge preservation：A randomized controlled trial[J]. Int J Implant Dent，2022，8(1):46. DOI：10.1186/s40729-022-00448-w.
[39]	Schlegel AK，Möhler H，Busch F，et al. Preclinical and clinical studies of a collagen membrane（Bio-Gide）[J]. Biomaterials，1997，18(7):535-538. DOI：10.1016/s0142-9612(96)00175-5.
[40]	Mo JS. The role of extracellular biophysical cues in modulating the Hippo-YAP pathway[J]. BMB Rep，2017，50(2):71-78. DOI：10.5483/bmbrep.2017.50.2.199.
[41]	Tonazzini I，Masciullo C，Savi E，et al. Neuronal contact guidance and YAP signaling on ultra-small nanogratings[J]. Sci Rep，2020，10(1):3742. DOI：10.1038/s41598-020-60745-5.
[42]	Basu S，Totty NF，Irwin MS，et al. Akt phosphorylates the Yes-associated protein，YAP，to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis[J]. Mol Cell，2003，11(1):11-23. DOI：10.1016/s1097-2765(02)00776-1.
[43]	Zhao B，Li L，Lei Q，et al. The Hippo-YAP pathway in organ size control and tumorigenesis：An updated version[J]. Genes Dev，2010，24(9):862-874. DOI：10.1101/gad.1909210.
[44]	Wang D，He J，Huang B，et al. Emerging role of the Hippo pathway in autophagy[J]. Cell Death Dis，2020，11(10):880. DOI：10.1038/s41419-020-03069-6.
[45]	Mosaddad SA，Salari Y，Amookhteh S，et al. Response to mechanical cues by interplay of yap/taz transcription factors and key mechanical checkpoints of the cell：A comprehensive review[J]. Cell Physiol Biochem，2021，55(1):33-60. DOI：10.33594/000000325.
[46]	Han P，Vaquette C，Abdal-Hay A，et al. The mechanosensing and global DNA methylation of human osteoblasts on MEW fibers[J]. Nanomaterials（Basel），2021，11(11):2943. DOI：10.3390/nano11112943.
[47]	Chiou G，Jui E，Rhea AC，et al. Scaffold architecture and matrix strain modulate mesenchymal cell and microvascular growth and development in a time dependent manner[J]. Cell Mol Bioeng，2020，13(5):507-526. DOI：10.1007/s12195-020-00648-7.
[48]	Elosegui-Artola A，Oria R，Chen Y，et al. Mechanical regulation of a molecular clutch defines force transmission and transduction in response to matrix rigidity[J]. Nat Cell Biol，2016，18(5):540-548. DOI：10.1038/ncb3336.
[49]	McKee C，Hong Y，Yao D，et al. Compression induced chondrogenic differentiation of embryonic stem cells in three-dimensional polydimethylsiloxane scaffolds[J]. Tissue Eng Part A，2017，23(9/10):426-435. DOI：10.1089/ten.TEA.2016.0376.
[50]	Totaro A，Panciera T，Piccolo S. YAP/TAZ upstream signals and downstream responses[J]. Nat Cell Biol，2018，20(8):888-899. DOI：10.1038/s41556-018-0142-z.
[51]	Feng Q，Gao H，Wen H，et al. Engineering the cellular mechanical microenvironment to regulate stem cell chondrogenesis：Insights from a microgel model[J]. Acta Biomater，2020，113:393-406. DOI：10.1016/j.actbio.2020.06.046.
[52]	Le V，Lee J，Chaterji S，et al. Syndecan-1 in mechanosensing of nanotopological cues in engineered materials[J]. Biomaterials，2018，155:13-24. DOI：10.1016/j.biomaterials.2017.11.007.
[53]	Jorgenson AJ，Choi KM，Sicard D，et al. TAZ activation drives fibroblast spheroid growth，expression of profibrotic paracrine signals，and context-dependent ECM gene expression[J]. Am J Physiol Cell Physiol，2017，312(3):C277-C285. DOI：10.1152/ajpcell.00205.2016.
[54]	Li L，Yang S，Xu L，et al. Nanotopography on titanium promotes osteogenesis via autophagy-mediated signaling between YAP and β-catenin[J]. Acta Biomater，2019，96:674-685. DOI：10.1016/j.actbio.2019.07.007.
[55]	Zhou Q，Lyu S，Bertrand AA，et al. Stiffness of nanoparticulate mineralized collagen scaffolds triggers osteogenesis via mechanotransduction and canonical wnt signaling[J]. Macromol Biosci，2021，21(3):e2000370. DOI：10.1002/mabi.202000370.
[56]	Shi W，Bian L，Wu Y，et al. Enhanced Bone Regeneration Using a ZIF-8-Loaded Fibrin Composite Scaffold[J]. Macromol Biosci，2022，22(3):e2100416. DOI：10.1002/mabi.202100416.
[57]	Xie M，Fritch M，He Y，et al. Dynamic loading enhances chondrogenesis of human chondrocytes within a biodegradable resilient hydrogel[J]. Biomater Sci，2021，9(14):5011-5024. DOI：10.1039/d1bm00413a.
[58]	Yang Y，Wang D，Zhang C，et al. Piezo1 mediates endothelial atherogenic inflammatory responses via regulation of YAP/TAZ activation[J]. Hum Cell，2022，35(1):51-62. DOI：10.1007/s13577-021-00600-5.
[59]	Pathak MM，Nourse JL，Tran T，et al. Stretch-activated ion channel Piezo1 directs lineage choice in human neural stem cells[J]. Proc Natl Acad Sci U S A，2014，111(45):16148-16153. DOI：10.1073/pnas.1409802111.
[60]	Bao L，Cui X，Wang X，et al. Carbon nanotubes promote the development of intestinal organoids through regulating extracellular matrix viscoelasticity and intracellular energy metabolism[J]. ACS Nano，2021，15(10):15858-15873. DOI：10.1021/acsnano.1c03707.
[61]	Mascharak S，Benitez PL，Proctor AC，et al. YAP-dependent mechanotransduction is required for proliferation and migration on native-like substrate topography[J]. Biomaterials，2017，115:155-166. DOI：10.1016/j.biomaterials.2016.11.019.
[62]	Chen L，Wu C，Wei D，et al. Biomimetic mineralized microenvironment stiffness regulated BMSCs osteogenic differentiation through cytoskeleton mediated mechanical signaling transduction[J]. Mater Sci Eng C Mater Biol Appl，2021，119:111613. DOI：10.1016/j.msec.2020.111613.
[63]	Xiang S，Li Z，Fritch MR，et al. Caveolin-1 mediates soft scaffold-enhanced adipogenesis of human mesenchymal stem cells[J]. Stem Cell Res Ther，2021，12(1):347. DOI：10.1186/s13287-021-02356-z.
[64]	Guo S，Debbi L，Zohar B，et al. Stimulating extracellular vesicles production from engineered tissues by mechanical forces[J]. Nano Lett，2021，21(6):2497-2504. DOI：10.1021/acs.nanolett.0c04834.

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Research progress of regulation of stem cell biological behavior by scaffold mechanical properties through Yes-associated protein signaling