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The Role of Mechanical Forces in Guiding Tissue Differentiation

  • Sean P. Sheehy
  • Kevin Kit ParkerEmail author
Chapter
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)

Abstract

Stem cell differentiation is regulated by a diverse array of extracellular cues. Recent evidence suggests that mechanical interactions between extracellular matrix (ECM) and cell surface receptors as well as physical interactions between neighboring cells play important roles in stem cell self-renewal and differentiation. It is also becoming clear that the ECM effects cellular behavior through many physical mechanisms, such as ECM geometry, elasticity, and the propagation of mechanical signals to intracellular compartments. Considerable effort is being targeted at developing biomaterials that exploit cellular microenvironments in guiding cells to desired phenotypes and organizing these into functional tissues. Improved understanding of the interactions between stem cells and their physical environment should yield new insight into the mechanisms governing their activity and allow the fabrication of artificial ECM to promote tissue development.

Keywords

Stem Cell Adherens Junction Stem Cell Differentiation Stem Cell Niche Notch Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

CAD

Computer-aided design

ECM

Extracellular matrix

LINC

Linker of nucleoskeleton and cytoskeleton

MRTFs

Myocardin-related transcription factors

MSCs

Mesenchymal stem cells

SRF

Serum response factor

STARS

Striated muscle activator of Rho signaling

References

  1. 1.
    Ingber DE (2006) Mechanical control of tissue morphogenesis during embryological development. Int J Dev Biol 50(2–3):255–266PubMedCrossRefGoogle Scholar
  2. 2.
    Ingber DE (2006) Cellular mechanotransduction: putting all the pieces together again. FASEB J 20(7):811–827PubMedCrossRefGoogle Scholar
  3. 3.
    Moore KA, Polte T, Huang S, Shi B, Alsberg E, Sunday ME, Ingber DE (2005) Control of basement membrane remodeling and epithelial branching morphogenesis in embryonic lung by Rho and cytoskeletal tension. Dev Dyn 232(2):268–281PubMedCrossRefGoogle Scholar
  4. 4.
    Ingber DE (2002) Mechanical signaling and the cellular response to extracellular matrix in angiogenesis and cardiovascular physiology. Circ Res 91(10):877–887PubMedCrossRefGoogle Scholar
  5. 5.
    Jamora C, DasGupta R, Kocieniewski P, Fuchs E (2003) Links between signal transduction, transcription and adhesion in epithelial bud development. Nature 422(6929):317–322. doi: 10.1038/nature01458 PubMedCrossRefGoogle Scholar
  6. 6.
    Kilian KA, Bugarija B, Lahn BT, Mrksich M (2010) Geometric cues for directing the differentiation of mesenchymal stem cells. Proc Natl Acad Sci USA 107(11):4872–4877PubMedCrossRefGoogle Scholar
  7. 7.
    Treiser MD, Yang EH, Gordonov S, Cohen DM, Androulakis IP, Kohn J, Chen CS, Moghe PV (2010) Cytoskeleton-based forecasting of stem cell lineage fates. Proc Natl Acad Sci USA 107(2):610–615PubMedCrossRefGoogle Scholar
  8. 8.
    Discher DE, Mooney DJ, Zandstra PW (2009) Growth factors, matrices, and forces combine and control stem cells. Science 324(5935):1673–1677. doi: 10.1126/science.1171643 PubMedCrossRefGoogle Scholar
  9. 9.
    Discher D, Dong C, Fredberg JJ, Guilak F, Ingber D, Janmey P, Kamm RD, Schmid-Schonbein GW, Weinbaum S (2009) Biomechanics: cell research and applications for the next decade. Ann Biomed Eng 37(5):847–859PubMedCrossRefGoogle Scholar
  10. 10.
    Ross RS, Borg TK (2001) Integrins and the myocardium. Circ Res 88(11):1112–1119PubMedCrossRefGoogle Scholar
  11. 11.
    Terracio L, Rubin K, Gullberg D, Balog E, Carver W, Jyring R, Borg TK (1991) Expression of collagen binding integrins during cardiac development and hypertrophy. Circ Res 68(3):734–744PubMedGoogle Scholar
  12. 12.
    Fuchs E, Tumbar T, Guasch G (2004) Socializing with the neighbors: stem cells and their niche. Cell 116(6):769–778PubMedCrossRefGoogle Scholar
  13. 13.
    Gjorevski N, Nelson CM (2009) Bidirectional extracellular matrix signaling during tissue morphogenesis. Cytokine Growth Factor Rev 20(5–6):459–465PubMedCrossRefGoogle Scholar
  14. 14.
    Wang N, Butler JP, Ingber DE (1993) Mechanotransduction across the cell surface and through the cytoskeleton. Science 260(5111):1124–1127PubMedCrossRefGoogle Scholar
  15. 15.
    Schwartz MA, Schaller MD, Ginsberg MH (1995) Integrins: emerging paradigms of signal transduction. Annu Rev Cell Dev Biol 11:549–599PubMedCrossRefGoogle Scholar
  16. 16.
    Chen CS, Mrksich M, Huang S, Whitesides GM, Ingber DE (1997) Geometric control of cell life and death. Science 276(5317):1425–1428PubMedCrossRefGoogle Scholar
  17. 17.
    Georges PC, Janmey PA (2005) Cell type-specific response to growth on soft materials. J Appl Physiol 98(4):1547–1553PubMedCrossRefGoogle Scholar
  18. 18.
    Engler AJ, Griffin MA, Sen S, Bonnemann CG, Sweeney HL, Discher DE (2004) Myotubes differentiate optimally on substrates with tissue-like stiffness: pathological implications for soft or stiff microenvironments. J Cell Biol 166(6):877–887PubMedCrossRefGoogle Scholar
  19. 19.
    Engler AJ, Sen S, Sweeney HL, Discher DE (2006) Matrix elasticity directs stem cell lineage specification. Cell 126(4):677–689. doi: 10.1016/j.cell.2006.06.044 PubMedCrossRefGoogle Scholar
  20. 20.
    Zajac AL, Discher DE (2008) Cell differentiation through tissue elasticity-coupled, myosin-driven remodeling. Curr Opin Cell Biol 20(6):609–615. doi: 10.1016/j.ceb.2008.09.006 PubMedCrossRefGoogle Scholar
  21. 21.
    Engler AJ, Carag-Krieger C, Johnson CP, Raab M, Tang HY, Speicher DW, Sanger JW, Sanger JM, Discher DE (2008) Embryonic cardiomyocytes beat best on a matrix with heart-like elasticity: scar-like rigidity inhibits beating. J Cell Sci 121(22):3794–3802. doi: 10.1242/jcs.029678 PubMedCrossRefGoogle Scholar
  22. 22.
    Nelson WJ, Nusse R (2004) Convergence of Wnt, beta-catenin, and cadherin pathways. Science 303(5663):1483–1487PubMedCrossRefGoogle Scholar
  23. 23.
    Liu Z, Tan JL, Cohen DM, Yang MT, Sniadecki NJ, Ruiz SA, Nelson CM, Chen CS (2010) Mechanical tugging force regulates the size of cell-cell junctions. Proc Natl Acad Sci USA 107(22):9944–9949PubMedCrossRefGoogle Scholar
  24. 24.
    Saffitz JE, Kleber AG (2004) Effects of mechanical forces and mediators of hypertrophy on remodeling of gap junctions in the heart. Circ Res 94(5):585–591PubMedCrossRefGoogle Scholar
  25. 25.
    Saffitz JE (2005) Dependence of electrical coupling on mechanical coupling in cardiac myocytes: insights gained from cardiomyopathies caused by defects in cell-cell connections. Ann N Y Acad Sci 1047:336–344PubMedCrossRefGoogle Scholar
  26. 26.
    Shanker AJ, Yamada K, Green KG, Yamada KA, Saffitz JE (2005) Matrix-protein-specific regulation of Cx43 expression in cardiac myocytes subjected to mechanical load. Circ Res 96(5):558–566PubMedCrossRefGoogle Scholar
  27. 27.
    Wong RCB, Pebay A, Nguyen LTV, Koh KLL, Pera MF (2004) Presence of functional gap junctions in human embryonic stem cells. Stem Cells 22(6):883–889PubMedCrossRefGoogle Scholar
  28. 28.
    Boni A, Urbanek K, Nascimbene A, Hosoda T, Zheng H, Delucchi F, Amano K, Gonzalez A, Vitale S, Ojaimi C, Rizzi R, Bolli R, Yutzey KE, Rota M, Kajstura J, Anversa P, Leri A (2008) Notch1 regulates the fate of cardiac progenitor cells. Proc Natl Acad Sci USA 105(40):15529–15534PubMedCrossRefGoogle Scholar
  29. 29.
    Bray SJ (2006) Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7(9):678–689PubMedCrossRefGoogle Scholar
  30. 30.
    Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R, Poser SW, Rueger MA, Bae S-K, Kittappa R, McKay RDG (2006) Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442(7104):823–826PubMedCrossRefGoogle Scholar
  31. 31.
    Wozniak MA, Chen CS (2009) Mechanotransduction in development: a growing role for contractility. Nat Rev Mol Cell Biol 10(1):34–43PubMedCrossRefGoogle Scholar
  32. 32.
    Kwon C, Qian L, Cheng P, Nigam V, Arnold J, Srivastava D (2009) A regulatory pathway involving Notch1/beta-catenin/Isl1 determines cardiac progenitor cell fate. Nat Cell Biol 11(8):951–957PubMedCrossRefGoogle Scholar
  33. 33.
    Fu J, Wang Y-K, Yang MT, Desai RA, Yu X, Liu Z, Chen CS (2010) Mechanical regulation of cell function with geometrically modulated elastomeric substrates. Nat Methods 7(9):733–736PubMedCrossRefGoogle Scholar
  34. 34.
    Guilak F, Cohen DM, Estes BT, Gimble JM, Liedtke W, Chen CS (2009) Control of stem cell fate by physical interactions with the extracellular matrix. Cell Stem Cell 5(1):17–26PubMedCrossRefGoogle Scholar
  35. 35.
    Parker KK, Brock AL, Brangwynne C, Mannix RJ, Wang N, Ostuni E, Geisse NA, Adams JC, Whitesides GM, Ingber DE (2002) Directional control of lamellipodia extension by constraining cell shape and orienting cell tractional forces. FASEB J 16(10):1195–1204PubMedCrossRefGoogle Scholar
  36. 36.
    Fletcher DA, Mullins D (2010) Cell mechanics and the cytoskeleton. Nature 463(7280):485–492. doi: 10.1038/nature08908 PubMedCrossRefGoogle Scholar
  37. 37.
    Huang S, Brangwynne CP, Parker KK, Ingber DE (2005) Symmetry-breaking in mammalian cell cohort migration during tissue pattern formation: role of random-walk persistence. Cell Motil Cytoskeleton 61(4):201–213PubMedCrossRefGoogle Scholar
  38. 38.
    Ruiz SA, Chen CS (2008) Emergence of patterned stem cell differentiation within multicellular structures. Stem Cells 26(11):2921–2927PubMedCrossRefGoogle Scholar
  39. 39.
    Huebsch N, Arany PR, Mao AS, Shvartsman D, Ali OA, Bencherif SA, Rivera-Feliciano J, Mooney DJ (2010) Harnessing traction-mediated manipulation of the cell/matrix interface to control stem-cell fate. Nat Mater 9(6):518–526. doi: 10.1038/nmat2732 PubMedCrossRefGoogle Scholar
  40. 40.
    McBeath R, Pirone DM, Nelson CM, Bhadriraju K, Chen CS (2004) Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell 6(4):483–495PubMedCrossRefGoogle Scholar
  41. 41.
    Bray M-A, Sheehy SP, Parker KK (2008) Sarcomere alignment is regulated by myocyte shape. Cell Motil Cytoskeleton 65(8):641–651PubMedCrossRefGoogle Scholar
  42. 42.
    Mammoto A, Connor KM, Mammoto T, Yung CW, Huh D, Aderman CM, Mostoslavsky G, Smith LEH, Ingber DE (2009) A mechanosensitive transcriptional mechanism that controls angiogenesis. Nature 457(7233):1103–1108PubMedCrossRefGoogle Scholar
  43. 43.
    Samarakoon R, Higgins PJ (2002) MEK/ERK pathway mediates cell-shape-dependent plasminogen activator inhibitor type 1 gene expression upon drug-induced disruption of the microfilament and microtubule networks. J Cell Sci 115(Pt 15):3093–3103PubMedGoogle Scholar
  44. 44.
    Olson EN, Nordheim A (2010) Linking actin dynamics and gene transcription to drive cellular motile functions. Nat Rev Mol Cell Biol 11(5):353–365PubMedCrossRefGoogle Scholar
  45. 45.
    Kuwahara K, Barrientos T, Pipes GCT, Li S, Olson EN (2005) Muscle-specific signaling mechanism that links actin dynamics to serum response factor. Mol Cell Biol 25(8):3173–3181PubMedCrossRefGoogle Scholar
  46. 46.
    Mack CP, Somlyo AV, Hautmann M, Somlyo AP, Owens GK (2001) Smooth muscle differentiation marker gene expression is regulated by RhoA-mediated actin polymerization. J Biol Chem 276(1):341–347PubMedCrossRefGoogle Scholar
  47. 47.
    Wang N, Tytell JD, Ingber DE (2009) Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus. Nat Rev Mol Cell Biol 10(1):75–82PubMedCrossRefGoogle Scholar
  48. 48.
    Maniotis AJ, Chen CS, Ingber DE (1997) Demonstration of mechanical connections between integrins, cytoskeletal filaments, and nucleoplasm that stabilize nuclear structure. Proc Natl Acad Sci USA 94(3):849–854PubMedCrossRefGoogle Scholar
  49. 49.
    Maniotis AJ, Bojanowski K, Ingber DE (1997) Mechanical continuity and reversible chromosome disassembly within intact genomes removed from living cells. J Cell Biochem 65(1):114–130PubMedCrossRefGoogle Scholar
  50. 50.
    Meshorer E, Misteli T (2006) Chromatin in pluripotent embryonic stem cells and differentiation. Nat Rev Mol Cell Biol 7(7):540–546PubMedCrossRefGoogle Scholar
  51. 51.
    Constantinescu D, Gray HL, Sammak PJ, Schatten GP, Csoka AB (2006) Lamin A/C expression is a marker of mouse and human embryonic stem cell differentiation. Stem Cells 24(1):177–185PubMedCrossRefGoogle Scholar
  52. 52.
    Pajerowski JD, Dahl KN, Zhong FL, Sammak PJ, Discher DE (2007) Physical plasticity of the nucleus in stem cell differentiation. Proc Natl Acad Sci USA 104(40):15619–15624PubMedCrossRefGoogle Scholar
  53. 53.
    Dahl KN, Ribeiro AJS, Lammerding J (2008) Nuclear shape, mechanics, and mechanotransduction. Circ Res 102(11):1307–1318PubMedCrossRefGoogle Scholar
  54. 54.
    Bray M-AP, Adams WJ, Geisse NA, Feinberg AW, Sheehy SP, Parker KK (2009) Nuclear morphology and deformation in engineered cardiac myocytes and tissues. Biomaterials 31(19):5143–5150CrossRefGoogle Scholar
  55. 55.
    Thomas CH, Collier JH, Sfeir CS, Healy KE (2002) Engineering gene expression and protein synthesis by modulation of nuclear shape. Proc Natl Acad Sci USA 99(4):1972–1977PubMedCrossRefGoogle Scholar
  56. 56.
    Huebsch N, Mooney DJ (2009) Inspiration and application in the evolution of biomaterials. Nature 462(7272):426–432. doi: 10.1038/nature08601 PubMedCrossRefGoogle Scholar
  57. 57.
    Chien KR, Domian IJ, Parker KK (2008) Cardiogenesis and the complex biology of regenerative cardiovascular medicine. Science 322(5907):1494–1497PubMedCrossRefGoogle Scholar
  58. 58.
    Jacot JG, Martin JC, Hunt DL (2010) Mechanobiology of cardiomyocyte development. J Biomech 43(1):93–98PubMedCrossRefGoogle Scholar
  59. 59.
    Mrksich M, Dike LE, Tien J, Ingber DE, Whitesides GM (1997) Using microcontact printing to pattern the attachment of mammalian cells to self-assembled monolayers of alkanethiolates on transparent films of gold and silver. Exp Cell Res 235(2):305–313PubMedCrossRefGoogle Scholar
  60. 60.
    Adams WJ, Pong T, Geisse NA, Sheehy SP, Parker KK (2007) Engineering design of a cardiac myocyte. J Computer-Aided Mater Des 14:19–29CrossRefGoogle Scholar
  61. 61.
    Bol M, Reese S, Parker K, Kuhl K (2008) Computational modeling of muscular thin films for cardiac repair. Comp Mech 43:535–544CrossRefGoogle Scholar
  62. 62.
    Latimer DC, Roth BJ, Parker KK (2003) Analytical model for predicting mechanotransduction effects in engineered cardiac tissue. Tissue Eng 9(2):283–289PubMedCrossRefGoogle Scholar
  63. 63.
    Mei Y, Saha K, Bogatyrev SR, Yang J, Hook AL, Kalcioglu ZI, Cho SW, Mitalipova M, Pyzocha N, Rojas F, Van Vliet KJ, Davies MC, Alexander MR, Langer R, Jaenisch R, Anderson DG (2010) Combinatorial development of biomaterials for clonal growth of human pluripotent stem cells. Nat Mater 9(9):768–778. doi: 10.1038/nmat2812 PubMedCrossRefGoogle Scholar
  64. 64.
    Chau Y, Luo Y, Cheung ACY, Nagai Y, Zhang SG, Kobler JB, Zeitels SM, Langer R (2008) Incorporation of a matrix metalloproteinase-sensitive substrate into self-assembling peptides – a model for biofunctional scaffolds. Biomaterials 29(11):1713–1719. doi: 10.1016/j.biomaterials.2007.11.046 PubMedCrossRefGoogle Scholar
  65. 65.
    Singhvi R, Kumar A, Lopez GP, Stephanopoulos GN, Wang DI, Whitesides GM, Ingber DE (1994) Engineering cell shape and function. Science 264(5159):696–698PubMedCrossRefGoogle Scholar
  66. 66.
    Lutolf MP, Hubbell JA (2005) Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering. Nat Biotechnol 23(1):47–55PubMedCrossRefGoogle Scholar
  67. 67.
    Kraehenbuehl TP, Zammaretti P, Van der Vlies AJ, Schoenmakers RG, Lutolf MP, Jaconi ME, Hubbell JA (2008) Three-dimensional extracellular matrix-directed cardioprogenitor differentiation: systematic modulation of a synthetic cell-responsive PEG-hydrogel. Biomaterials 29(18):2757–2766PubMedCrossRefGoogle Scholar
  68. 68.
    Eschenhagen T, Zimmermann WH (2005) Engineering myocardial tissue. Circ Res 97(12):1220–1231PubMedCrossRefGoogle Scholar
  69. 69.
    Feinberg AW, Parker KK (2010) Surface-initiated assembly of protein nanofabrics. Nano Lett 10(6):2184–2191PubMedCrossRefGoogle Scholar
  70. 70.
    Badrossamay MR, McIlwee HA, Goss JA, Parker KK (2010) Nanofiber assembly by rotary jet-spinning. Nano Lett 10(6):2257–2261PubMedCrossRefGoogle Scholar
  71. 71.
    Huh D, Matthews BD, Mammoto A, Montoya-Zavala M, Hsin HY, Ingber DE (2010) Reconstituting organ-level lung functions on a chip. Science 328(5986):1662–1668PubMedCrossRefGoogle Scholar
  72. 72.
    Feinberg AW, Feigel A, Shevkoplyas SS, Sheehy S, Whitesides GM, Parker KK (2007) Muscular thin films for building actuators and powering devices. Science 317(5843):1366–1370PubMedCrossRefGoogle Scholar
  73. 73.
    Domian IJ, Chiravuri M, van der Meer P, Feinberg AW, Shi X, Shao Y, Wu SM, Parker KK, Chien KR (2009) Generation of functional ventricular heart muscle from mouse ventricular progenitor cells. Science 326(5951):426–429PubMedCrossRefGoogle Scholar
  74. 74.
    Alford PW, Feinberg AW, Sheehy SP, Parker KK (2010) Biohybrid thin films for measuring contractility in engineered cardiovascular muscle. Biomaterials 31(13):3613–3621PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied SciencesHarvard UniversityCambridgeUSA

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