The tight regulation of cytoskeleton dynamics is required for a number of cellular processes, including migration, division and differentiation. YAP-TEAD respond to cell-cell interaction and to substrate mechanics and, among their downstream effects, prompt focal adhesion (FA) gene transcription, thus contributing to FA-cytoskeleton stability. This activity is key to the definition of adult cell mechanical properties and function. Its regulation and role in pluripotent stem cells are poorly understood. Human PSCs display a sustained basal YAP-driven transcriptional activity despite they grow in very dense colonies, indicating these cells are insensitive to contact inhibition. PSC inability to perceive cell-cell interactions can be restored by tampering with Tankyrase enzyme, thus favouring AMOT inhibition of YAP function. YAP-TEAD complex is promptly inactivated when germ layers are specified, and this event is needed to adjust PSC mechanical properties in response to physiological substrate stiffness. By providing evidence that YAP-TEAD1 complex targets key genes encoding for proteins involved in cytoskeleton dynamics, we suggest that substrate mechanics can direct PSC specification by influencing cytoskeleton arrangement and intracellular tension. We propose an aberrant activation of YAP-TEAD1 axis alters PSC potency by inhibiting cytoskeleton dynamics, thus paralyzing the changes in shape requested for the acquisition of the given phenotype.

Central European Institute of Technology Masaryk University CZ 62500 Brno Czech Republic

Competence Center for Mechanobiology in Regenerative Medicine INTERREG ATCZ133 CZ 62500 Brno Czech Republic

Czech Academy of Sciences Institute of Theoretical and Applied Mechanics 190 00 Prague 9 Czech Republic

Department of Biomaterials Science Institute of Dentistry University of Turku FI 20014 Turku Finland

Department of Development and Regeneration KU Leuven 3000 Leuven Belgium

Department of Life Sciences Cattinara University Hospital Trieste University 1 34149 Trieste Italy

Faculty of Medicine Department of Biology Masaryk University CZ 62500 Brno Czech Republic

Institute of Nanotechnology National Research Council c o Campus EcoTekne via Monteroni 73100 Lecce Italy

International Clinical Research Center of St Anne's University Hospital CZ 65691 Brno Czech Republic

Università Campus Bio Medico di Roma Rome Italy

Zobrazit více v PubMed

McBeath R, Pirone DM, Nelson CM, Bhadriraju K, Chen CS. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell. 2004;6:483–95. PubMed

Handorf AM, Zhou Y, Halanski MA, Li W-J. Tissue stiffness dictates development, homeostasis, and disease progression. Organogenesis. 2015;11:1–15. PubMed PMC

Petridou NI, Spiró Z, Heisenberg CP. Multiscale force sensing in development. Nat Cell Biol. 2017;19:581–8. PubMed

Wang X, Zhang Z, Tao H, Liu J, Hopyan S, Sun Y. Characterizing inner pressure and stiffness of trophoblast and inner cell mass of blastocysts. Biophys J. 2018;115:2443–50. PubMed PMC

Maître JL, Turlier H, Illukkumbura R, Eismann B, Niwayama R, Nédélec F, et al. Asymmetric division of contractile domains couples cell positioning and fate specification. Nature. 2016;536:344–8. PubMed PMC

Hirate Y, Hirahara S, Inoue K, Suzuki A, Alarcon VB, Akimoto K, et al. Polarity-dependent distribution of angiomotin localizes hippo signaling in preimplantation embryos. Curr Biol. 2013;23:1181–94. PubMed PMC

Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW, Jaenisch R, et al. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol. 2007;17:2054–60. PubMed

Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA, et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell. 2007;130:1120–33. PubMed PMC

Yu F-X, Zhao B, Guan K-L. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell. 2015;163:811–28. PubMed PMC

Varelas X. The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease. Development. 2014;141:1614–26. PubMed

Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, et al. Role of YAP/TAZ in mechanotransduction. Nature. 2011;474:179–83. PubMed

Martino F, Perestrelo AR, Vinarský V, Pagliari S, Forte G. Mechanotransduction: from tension to function. Front Physiol. 2018;5:824. PubMed PMC

Zhao B, Ye X, Yu J, Li L, Li W, Li S, et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 2008;22:1962–71. PubMed PMC

Gumbiner BM, Kim N-G. The Hippo-YAP signaling pathway and contact inhibition of growth. J Cell Sci. 2014;127:709–17. PubMed PMC

Mosqueira D, Pagliari S, Uto K, Ebara M, Romanazzo S, Escobedo-Lucea C, et al. Hippo pathway effectors control cardiac progenitor cell fate by acting as dynamic sensors of substrate mechanics and nanostructure. ACS Nano. 2014;8:2033–47. PubMed

Oliver-De La Cruz J, Nardone G, Vrbsky J, Pompeiano A, Perestrelo AR, Capradossi F, et al. Substrate mechanics controls adipogenesis through YAP phosphorylation by dictating cell spreading. Biomaterials. 2019;205:64–80. PubMed

Nardone G, Oliver-De La Cruz J, Vrbsky J, Martini C, Pribyl J, Skládal P, et al. YAP regulates cell mechanics by controlling focal adhesion assembly. Nat Commun. 2017;8:15321. PubMed PMC

Chung H, Lee BK, Uprety N, Shen W, Lee J, Kim J. Yap1 is dispensable for self-renewal but required for proper differentiation of mouse embryonic stem (ES) cells. EMBO Rep. 2016;17:519–29. PubMed PMC

Lian I, Kim J, Okazawa H, Zhao J, Zhao B, Yu J, et al. The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation. Genes Dev. 2010;24:1106–18. PubMed PMC

Qin H, Blaschke K, Wei G, Ohi Y, Blouin L, Qi Z, et al. Transcriptional analysis of pluripotency reveals the Hippo pathway as a barrier to reprogramming. Hum Mol Genet. 2012;21:2054–67. PubMed PMC

Panciera T, Azzolin L, Fujimura A, Di Biagio D, Frasson C, Bresolin S, et al. Induction of expandable tissue-specific stem/progenitor cells through transient expression of YAP/TAZ. Cell Stem Cell. 2016;19:725–37. PubMed PMC

Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell. 2006;126:677–89. PubMed

Bhana B, Iyer RK, Chen WL, Zhao R, Sider KL, Likhitpanichkul M, et al. Influence of substrate stiffness on the phenotype of heart cells. Biotechnol Bioeng. 2010;105:1148–60. PubMed

Koser DE, Thompson AJ, Foster SK, Dwivedy A, Pillai EK, Sheridan GK, et al. Mechanosensing is critical for axon growth in the developing brain. Nat Neurosci. 2016;19:1592–8. PubMed PMC

Chang TY, Chen C, Lee M, Chang YC, Lu CH, Lu ST, et al. Paxillin facilitates timely neurite initiation on soft-substrate environments by interacting with the endocytic machinery. Elife. 2017;6:e31101. PubMed PMC

Patel NR, Bole M, Chen C, Hardin CC, Kho AT, Mih J, et al. Cell elasticity determines macrophage function. PLoS ONE. 2012;7:e41024. PubMed PMC

Meng Z, Qiu Y, Lin KC, Kumar A, Placone JK, Fang C, et al. RAP2 mediates mechanoresponses of the Hippo pathway. Nature. 2018;560:655–60. PubMed PMC

Elosegui-Artola A, Andreu I, Beedle AEM, Lezamiz A, Uroz M, Kosmalska AJ, et al. Force triggers YAP nuclear entry by regulating transport across nuclear pores. Cell. 2017;171:1397. PubMed

Zanconato F, Forcato M, Battilana G, Azzolin L, Quaranta E, Bodega B, et al. Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat Cell Biol. 2015;17:1218–27. PubMed PMC

Calvo F, Ege N, Grande-Garcia A, Hooper S, Jenkins RP, Chaudhry SI, et al. Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat Cell Biol. 2013;15:637–46. PubMed PMC

Hashimoto M, Sasaki H. Epiblast formation by TEAD-YAP-dependent expression of pluripotency factors and competitive elimination of unspecified cells. Dev Cell. 2019;50:139. PubMed

Nishioka N, Inoue K, Adachi K, Kiyonari H, Ota M, Ralston A, et al. Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass. Dev Cell. 2009;16:398–410. PubMed

Qin H, Hejna M, Liu Y, Percharde M, Wossidlo M, Blouin L, et al. YAP induces human naive pluripotency. Cell Rep. 2016;14:2301–12. PubMed PMC

Heallen T, Zhang M, Wang J, Bonilla-Claudio M, Klysik E, Johnson RL, et al. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science. 2011;332:458–61. PubMed PMC

Zhao B, Li L, Lu Q, Wang LH, Liu CY, Lei Q, et al. Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein. Genes Dev. 2011;25:51–63. PubMed PMC

Zaltsman Y, Masuko S, Bensen JJ, Kiessling LL. Angiomotin regulates YAP localization during neural differentiation of human pluripotent stem cells. Stem Cell Rep. 2019;12:869–77. PubMed PMC

Wang W, Li N, Li X, Tran MK, Han X, Chen J. Tankyrase inhibitors target YAP by stabilizing angiomotin family proteins. Cell Rep. 2015;13:524–32. PubMed PMC

Tavares S, Vieira AF, Taubenberger AV, Araújo M, Martins NP, Brás-Pereira C, et al. Actin stress fiber organization promotes cell stiffening and proliferation of pre-invasive breast cancer cells. Nat Commun. 2017;8:15237. PubMed PMC

Taira K, Umikawa M, Takei K, Myagmar BE, Shinzato M, Machida N, et al. The Traf2- and Nck-interacting kinase as a putative effector of Rap2 to regulate actin cytoskeleton. J Biol Chem. 2004;279:49488–96. PubMed

Papakonstanti EA, Stournaras C. Association of PI-3 kinase with PAK1 leads to actin phosphorylation and cytoskeletal reorganization. Mol Biol Cell. 2002;13:2946–62. PubMed PMC

Lv Z, Hu M, Ren X, Fan M, Zhen J, Chen L, et al. Fyn mediates high glucose-induced actin cytoskeleton reorganization of podocytes via promoting ROCK activation in vitro. J Diabetes Res. 2016;2016:5671803. PubMed PMC

Woeller CF, O’Loughlin CW, Pollock SJ, Thatcher TH, Feldon SE, Phipps RP. Thy1 (CD90) controls adipogenesis by regulating activity of the Src family kinase, Fyn. FASEB J. 2015;29:920–31. PubMed PMC

Yuan A, Rao MV, Veeranna, Nixon RA. Neurofilaments and neurofilament proteins in health and disease. Cold Spring Harb Perspect Bio. 2017;9:a018309. PubMed PMC

Wu JQ, Kuhn JR, Kovar DR, Pollard TD. Spatial and temporal pathway for assembly and constriction of the contractile ring in fission yeast cytokinesis. Dev Cell. 2003;5:723–34. PubMed

Holzinger A. Jasplakinolide: an actin-specific reagent that promotes actin polymerization. Methods Mol Biol. 2009;586:71–87. PubMed

Mandriota N, Friedsam C, Jones-Molina JA, Tatem KV, Ingber DE, Sahin O. Cellular nanoscale stiffness patterns governed by intracellular forces. Nat Mater. 2019;18:1071–7. PubMed PMC

Grashoff C, Hoffman BD, Brenner MD, Zhou R, Parsons M, Yang MT, et al. Measuring mechanical tension across vinculin reveals regulation of focal adhesion dynamics. Nature. 2010;466:263–6. PubMed PMC

Plotnikov SV, Sabass B, Schwarz US, Waterman CM. High-resolution traction force microscopy. Methods Cell Biol. 2014;123:367–94. PubMed PMC

Hogrebe NJ, Augsornworawat P, Maxwell KG, Velazco-Cruz L, Millman JR. Targeting the cytoskeleton to direct pancreatic differentiation of human pluripotent stem cells. Nat Biotechnol. 2020;38:460–70. PubMed PMC

Sordella R, Jiang W, Chen GC, Curto M, Settleman J. Modulation of Rho GTPase signaling regulates a switch between adipogenesis and myogenesis. Cell. 2003;113:147–58. PubMed

Totaro A, Castellan M, Battilana G, Zanconato F, Azzolin L, Giulitti S, et al. YAP/TAZ link cell mechanics to Notch signalling to control epidermal stem cell fate. Nat Commun. 2017;8:15206. PubMed PMC

Zanconato F, Cordenonsi M, Piccolo S. YAP/TAZ at the roots of cancer. Cancer Cell. 2016;29:783–803. PubMed PMC

Qiao Y, Chen J, Lim YB, Finch-Edmondson ML, Seshachalam VP, Qin L, et al. YAP regulates actin dynamics through ARHGAP29 and promotes metastasis. Cell Rep. 2017;19:1495–502. PubMed

Morikawa Y, Zhang M, Heallen T, Leach J, Tao G, Xiao Y, et al. Actin cytoskeletal remodeling with protrusion formation is essential for heart regeneration in Hippo-deficient mice. Sci Signal. 2015;8:ra41. PubMed PMC

LeClaire LL, Rana M, Baumgartner M, Barber DL. The Nck-interacting kinase NIK increases Arp2/3 complex activity by phosphorylating the Arp2 subunit. J Cell Biol. 2015;208:61–170. PubMed PMC

Xia S, Lim YB, Zhang Z, Wang Y, Zhang S, Lim CT, et al. Nanoscale architecture of the cortical actin cytoskeleton in embryonic stem cells. Cell Rep. 2019;28:1251. PubMed

Mason DE, Collins JM, Dawahare JH, Nguyen TD, Lin Y, Voytik-Harbin CL, et al. YAP and TAZ limit cytoskeletal and focal adhesion maturation to enable persistent cell motility. J Cell Biol. 2019;218:1369–89. PubMed PMC

Regulation of Cell-Nanoparticle Interactions through Mechanobiology

YAP Signaling Regulates the Cellular Uptake and Therapeutic Effect of Nanoparticles

Generation and maturation of human iPSC-derived 3D organotypic cardiac microtissues in long-term culture

A primer to traction force microscopy