iBet uBet web content aggregator. Adding the entire web to your favor.
iBet uBet web content aggregator. Adding the entire web to your favor.



Link to original content: https://doi.org/10.1038/nrm.2017.108
Mechanical forces direct stem cell behaviour in development and regeneration | Nature Reviews Molecular Cell Biology
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanical forces direct stem cell behaviour in development and regeneration

Nature Reviews Molecular Cell Biology volume 18, pages 728–742 (2017)Cite this article

Subjects

Key Points

  • Stem cells are regulated by cell-intrinsic and cell-extrinsic forces in development, homeostasis and regeneration.

  • Mechanical tension regulates early embryogenesis ex vivo in embryoid self-organization, germ-band elongation, invagination and dorsal closure, and sorting of the germ layers.

  • During development, mechanical forces regulate the generation of organ systems by directing the specification and expansion of stem cells, as well as re-organizing the extracellular matrix that begins to accumulate in embryonic tissues.

  • Synthetic matrices enable the control of biophysical properties of the stem cell niche in order to test specific hypotheses on how mechanical cues regulate stem cells.

  • Synthetic matrices have been used to demonstrate how mechanical cues, such as stiffness and viscoelasticity, as well as externally applied mechanical loads, control stem cell self-renewal and proliferation, differentiation and organoid formation.

  • Externally applied mechanical forces can stimulate stem cells to promote tissue regeneration.

Abstract

Stem cells and their local microenvironment, or niche, communicate through mechanical cues to regulate cell fate and cell behaviour and to guide developmental processes. During embryonic development, mechanical forces are involved in patterning and organogenesis. The physical environment of pluripotent stem cells regulates their self-renewal and differentiation. Mechanical and physical cues are also important in adult tissues, where adult stem cells require physical interactions with the extracellular matrix to maintain their potency. In vitro, synthetic models of the stem cell niche can be used to precisely control and manipulate the biophysical and biochemical properties of the stem cell microenvironment and to examine how the mode and magnitude of mechanical cues, such as matrix stiffness or applied forces, direct stem cell differentiation and function. Fundamental insights into the mechanobiology of stem cells also inform the design of artificial niches to support stem cells for regenerative therapies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Stem cells exert forces and are subject to external forces, which regulate their intracellular signalling pathways.
Figure 2: Mechanobiology during early development.
Figure 3: Material systems to study stem cell mechanobiology.
Figure 4: Three-dimensional synthetic niches physically confine stem cells and present mechanical cues that impact cell behaviour and fate through forces.
Figure 5: Tissue regeneration can be improved by exploiting stem cell mechanobiology.

Similar content being viewed by others

References

  1. Steinberg, M. S. Reconstruction of tissues by dissociated cells. Science 141, 401–408 (1963).

    Article  PubMed  CAS  Google Scholar 

  2. Maître, J.-L. et al. Asymmetric division of contractile domains couples cell positioning and fate specification. Nature 536, 344–348 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Ninomiya, H. & Winklbauer, R. Epithelial coating controls mesenchymal shape change through tissue-positioning effects and reduction of surface-minimizing tension. Nat. Cell Biol. 10, 61–69 (2008).

    Article  PubMed  CAS  Google Scholar 

  4. Bertet, C., Sulak, L. & Lecuit, T. Myosin-dependent junction remodelling controls planar cell intercalation and axis elongation. Nature 429, 667–671 (2004). This study shows that planar remodelling of cell–cell junctions in embryonic tissue is driven by intrinsic local forces, which are required for germ-band elongation during embryonic development.

    Article  PubMed  CAS  Google Scholar 

  5. Beloussov, L. V., Dorfman, J. G. & Cherdantzev, V. G. Mechanical stresses and morphological patterns in amphibian embryos. J. Embryol. Exp. Morphol. 34, 559–574 (1975).

    PubMed  CAS  Google Scholar 

  6. Rauzi, M., Verant, P., Lecuit, T. & Lenne, P. F. Nature and anisotropy of cortical forces orienting Drosophila tissue morphogenesis. Nat. Cell Biol. 10, 1401–1410 (2008).

    Article  PubMed  CAS  Google Scholar 

  7. Grill, S. W., Gonczy, P., Stelzer, E. H. & Hyman, A. A. Polarity controls forces governing asymmetric spindle positioning in the Caenorhabditis elegans embryo. Nature 409, 630–633 (2001).

    Article  PubMed  CAS  Google Scholar 

  8. Colombo, K. et al. Translation of polarity cues into asymmetric spindle positioning in Caenorhabditis elegans embryos. Science 300, 1957–1961 (2003).

    Article  PubMed  CAS  Google Scholar 

  9. Fernandez-Gonzalez, R., Simoes, S. D., Roper, J. C., Eaton, S. & Zallen, J. A. Myosin II dynamics are regulated by tension in intercalating cells. Dev. Cell 17, 736–743 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Kumar, S. et al. Viscoelastic retraction of single living stress fibers and its impact on cell shape, cytoskeletal organization, and extracellular matrix mechanics. Biophys. J. 90, 3762–3773 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Buckley, C. D. et al. The minimal cadherin-catenin complex binds to actin filaments under force. Science 346, 1254211 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Corrigall, D., Walther, R. F., Rodriguez, L., Fichelson, P. & Pichaud, F. Hedgehog signaling is a principal inducer of myosin-II-driven cell ingression in Drosophila epithelia. Dev. Cell 13, 730–742 (2007).

    Article  PubMed  CAS  Google Scholar 

  13. Martin, A. C., Kaschube, M. & Wieschaus, E. F. Pulsed contractions of an actin-myosin network drive apical constriction. Nature 457, 495–499 (2009).

    Article  PubMed  CAS  Google Scholar 

  14. Pouille, P. A., Ahmadi, P., Brunet, A. C. & Farge, E. Mechanical signals trigger myosin II redistribution and mesoderm invagination in Drosophila embryos. Sci. Signal. 2, 8 (2009).

    Article  CAS  Google Scholar 

  15. Krieg, M. et al. Tensile forces govern germ-layer organization in zebrafish. Nat. Cell Biol. 10, 429–436 (2008).

    Article  PubMed  CAS  Google Scholar 

  16. Solon, J., Kaya-Copur, A., Colombelli, J. & Brunner, D. Pulsed forces timed by a ratchet-like mechanism drive directed tissue movement during dorsal closure. Cell 137, 1331–1342 (2009).

    Article  PubMed  Google Scholar 

  17. Watanabe, K. et al. A ROCK inhibitor permits survival of dissociated human embryonic stem cells. Nat. Biotechnol. 25, 681–686 (2007).

    Article  PubMed  CAS  Google Scholar 

  18. Nonaka, S., Shiratori, H., Saijoh, Y. & Hamada, H. Determination of left-right patterning of the mouse embryo by artificial nodal flow. Nature 418, 96–99 (2002).

    Article  PubMed  CAS  Google Scholar 

  19. Tanaka, Y., Okada, Y. & Hirokawa, N. FGF-induced vesicular release of Sonic hedgehog and retinoic acid in leftward nodal flow is critical for left-right determination. Nature 435, 172–177 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Cosgrove, B. D. et al. N-Cadherin adhesive interactions modulate matrix mechanosensing and fate commitment of mesenchymal stem cells. Nat. Mater. 15, 1297–1306 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Kalson, N. S. et al. A structure-based extracellular matrix expansion mechanism of fibrous tissue growth. eLife 4, 1–22 (2015).

    Article  Google Scholar 

  22. Galbraith, C. G., Yamada, K. M. & Sheetz, M. P. The relationship between force and focal complex development. J. Cell Biol. 159, 695–705 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Elosegui-Artola, A. et al. Rigidity sensing and adaptation through regulation of integrin types. Nat. Mater. 13, 631–637 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Shyer, A. E. et al. Emergent cellular self-organization and mechanosensation initiate follicle pattern in the avian skin. Science 357, 811–815 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Petridou, N. I., Spiro, Z. & Heisenberg, C.-P. Multiscale force sensing in development. Nat. Cell Biol. 19, 581–588 (2017).

    Article  PubMed  CAS  Google Scholar 

  26. Desprat, N., Supatto, W., Pouille, P. A., Beaurepaire, E. & Farge, E. Tissue deformation modulates twist expression to determine anterior midgut differentiation in Drosophila embryos. Dev. Cell 15, 470–477 (2008).

    Article  PubMed  CAS  Google Scholar 

  27. Yang, Y., Beqaj, S., Kemp, P., Ariel, I. & Schuger, L. Stretch-induced alternative splicing of serum response factor promotes bronchial myogenesis and is defective in lung hypoplasia. J. Clin. Invest. 106, 1321–1330 (2000).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Hove, J. R. et al. Intracardiac fluid forces are an essential epigenetic factor for embryonic cardiogenesis. Nature 421, 172–177 (2003). In this work, the intracardiac high-shear flow in zebrafish embryos is characterized, demonstrating that perturbations in fluid flow can result in developmental anomalies that are similar to defects observed in patients with congenital heart disease.

    Article  PubMed  CAS  Google Scholar 

  29. Adamo, L. et al. Biomechanical forces promote embryonic haematopoiesis. Nature 459, 1131–1135 (2009). This study establishes the role of pulsatile fluid shear stress in haematopoietic development by mimicking forces exerted on embryonic vasculature and demonstrating increased expression of RUNX1 , which is a master regulator of haematopoiesis.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. North, T. E. et al. Hematopoietic stem cell development is dependent on blood flow. Cell 137, 736–748 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Nauli, S. M. et al. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat. Genet. 33, 129–137 (2003).

    Article  PubMed  CAS  Google Scholar 

  32. Nowlan, N. C., Murphy, P. & Prendergast, P. J. A dynamic pattern of mechanical stimulation promotes ossification in avian embryonic long bones. J. Biomech. 41, 249–258 (2008).

    Article  PubMed  Google Scholar 

  33. Daley, W. P., Gulfo, K. M., Sequeira, S. J. & Larsen, M. Identification of a mechanochemical checkpoint and negative feedback loop regulating branching morphogenesis. Dev. Biol. 336, 169–182 (2009). This study establishes the role of mechanical forces in regulating the initiation and propagation of clefting during epithelial branching morphogenesis, mediated through actomyosin contractility.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Daley, W. P., Kohn, J. M. & Larsen, M. A. Focal adhesion protein-based mechanochemical checkpoint regulates cleft progression during branching morphogenesis. Dev. Dyn. 240, 2069–2083 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Alcaraz, J. et al. Laminin and biomimetic extracellular elasticity enhance functional differentiation in mammary epithelia. EMBO J. 27, 2829–2838 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Fischer, R. S., Gardel, M., Ma, X. F., Adelstein, R. S. & Waterman, C. M. Local cortical tension by myosin II guides 3D endothelial cell branching. Curr. Biol. 19, 260–265 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Elliott, H. et al. Myosin II controls cellular branching morphogenesis and migration in three dimensions by minimizing cell-surface curvature. Nat. Cell Biol. 17, 137–147 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Mammoto, A. et al. A mechanosensitive transcriptional mechanism that controls angiogenesis. Nature 457, 1103–1108 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Song, X. Q., Zhu, C. H., Doan, C. & Xie, T. Germline, stem cells anchored by adherens junctions in the Drosophila ovary niches. Science 296, 1855–1857 (2002).

    Article  PubMed  CAS  Google Scholar 

  40. Tanentzapf, G., Devenport, D., Godt, D. & Brown, N. H. Integrin-dependent anchoring of a stem-cell niche. Nat. Cell Biol. 9, 1413–1418 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Zhu, A. J., Haase, I. & Watt, F. M. Signaling via β1 integrins and mitogen-activated protein kinase determines human epidermal stem cell fate in vitro. Proc. Natl Acad. Sci. USA 96, 6728–6733 (1999).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Rompolas, P., Mesa, K. R. & Greco, V. Spatial organization within a niche as a determinant of stem-cell fate. Nature 502, 513–518 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Kahn, J. et al. Muscle contraction is necessary to maintain joint progenitor cell fate. Dev. Cell 16, 734–743 (2009).

    Article  PubMed  CAS  Google Scholar 

  44. Huebsch, N. et al. Harnessing traction-mediated manipulation of the cell/matrix interface to control stem-cell fate. Nat. Mater. 9, 518–526 (2010). Using a well-controlled 3D physical environment, this study shows that matrix stiffness can direct stem cell fate in 3D culture.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Khetan, S. et al. Degradation-mediated cellular traction directs stem cell fate in covalently crosslinked three-dimensional hydrogels. Nat. Mater. 12, 458–465 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Rape, A. D., Zibinsky, M., Murthy, N. & Kumar, S. A synthetic hydrogel for the high-throughput study of cell–ECM interactions. Nat. Commun. 6, 8129 (2015).

    Article  PubMed  Google Scholar 

  47. Chaudhuri, O. et al. Hydrogels with tunable stress relaxation regulate stem cell fate and activity. Nat. Mater. 15, 326–334 (2016). By manipulating the stress relaxation behaviour of synthetic matrices, this study demonstrated that stem cell fate is regulated by time-dependent, or viscoelastic, properties of their physical environment.

    Article  PubMed  CAS  Google Scholar 

  48. Das, R. K., Gocheva, V., Hammink, R., Zouani, O. F. & Rowan, A. E. Stress-stiffening-mediated stem-cell commitment switch in soft responsive hydrogels. Nat. Mater. 15, 318–325 (2016).

    Article  PubMed  CAS  Google Scholar 

  49. Grinnell, F., Ho, C.-H., Tamariz, E., Lee, D. J. & Skuta, G. Dendritic fibroblasts in three-dimensional collagen matrices. Mol. Biol. Cell 14, 384–395 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Prewitz, M. C. et al. Tightly anchored tissue-mimetic matrices as instructive stem cell microenvironments. Nat. Methods 10, 788–794 (2013).

    Article  PubMed  CAS  Google Scholar 

  51. Beachley, V. Z. et al. Tissue matrix arrays for high-throughput screening and systems analysis of cell function. Nat. Methods 12, 1197–1204 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Wen, J. H. et al. Interplay of matrix stiffness and protein tethering in stem cell differentiation. Nat. Mater. 13, 979–987 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Trappmann, B. et al. Extracellular-matrix tethering regulates stem-cell fate. Nat. Mater. 11, 642–649 (2012).

    Article  PubMed  CAS  Google Scholar 

  54. Engler, A. J., Sen, S., Sweeney, H. L. & Discher, D. E. Matrix elasticity directs stem cell lineage specification. Cell 126, 677–689 (2006). This study shows that the lineage of MSCs can be controlled by the elasticity of the substrate to which they are adhered.

    Article  PubMed  CAS  Google Scholar 

  55. Gjorevski, N. et al. Designer matrices for intestinal stem cell and organoid culture. Nature 539, 560–564 (2016). This study describes a synthetic replacement for Matrigel that enhanced intestinal stem cell expansion through mechanotransduction and could control organoid formation.

    Article  PubMed  CAS  Google Scholar 

  56. Mohammadi, H., Arora, P. D., Simmons, C. A., Janmey, P. A. & McCulloch, C. A. Inelastic behaviour of collagen networks in cell–matrix interactions and mechanosensation. J. R. Soc. Interface 12, 20141074 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Jasinoski, S. C. & Reddy, B. D. Mechanics of cranial sutures during simulated cyclic loading. J. Biomech. 45, 2050–2054 (2012).

    Article  PubMed  CAS  Google Scholar 

  58. Mahadik, B. P., Bharadwaj, N. A. K., Ewoldt, R. H. & Harley, B. A. C. Regulating dynamic signaling between hematopoietic stem cells and niche cells via a hydrogel matrix. Biomaterials 125, 54–64 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Rowley, J. A., Madlambayan, G. & Mooney, D. J. Alginate hydrogels as synthetic extracellular matrix materials. Biomaterials 20, 45–53 (1999).

    Article  PubMed  CAS  Google Scholar 

  60. Kong, H.-J., Lee, K. Y. & Mooney, D. J. Decoupling the dependence of rheological/mechanical properties of hydrogels from solids concentration. Polymer 43, 6239–6246 (2002).

    Article  CAS  Google Scholar 

  61. Benoit, D. S. W., Schwartz, M. P., Durney, A. R. & Anseth, K. S. Small functional groups for controlled differentiation of hydrogel-encapsulated human mesenchymal stem cells. Nat. Mater. 7, 816–823 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Gobaa, S. et al. Artificial niche microarrays for probing single stem cell fate in high throughput. Nat. Methods 8, 949–955 (2011).

    Article  PubMed  CAS  Google Scholar 

  63. Zhao, X., Huebsch, N., Mooney, D. J. & Suo, Z. Stress-relaxation behavior in gels with ionic and covalent crosslinks. J. Appl. Phys. 107, 63509 (2010).

    Article  PubMed  CAS  Google Scholar 

  64. Kasper, G. et al. Matrix metalloprotease activity is an essential link between mechanical stimulus and mesenchymal stem cell behavior. Stem Cells 25, 1985–1994 (2007).

    Article  PubMed  CAS  Google Scholar 

  65. Fonseca, K. B. et al. Injectable MMP-sensitive alginate hydrogels as hMSC delivery systems. Biomacromolecules 15, 380–390 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Boontheekul, T., Kong, H. J. & Mooney, D. J. Controlling alginate gel degradation utilizing partial oxidation and bimodal molecular weight distribution. Biomaterials 26, 2455–2465 (2005).

    Article  PubMed  CAS  Google Scholar 

  67. Ho, F. C., Zhang, W., Li, Y. Y. & Chan, B. P. Mechanoresponsive, omni-directional and local matrix-degrading actin protrusions in human mesenchymal stem cells microencapsulated in a 3D collagen matrix. Biomaterials 53, 392–405 (2015).

    Article  PubMed  CAS  Google Scholar 

  68. Ye, K. et al. Matrix Stiffness and nanoscale spatial organization of cell-adhesive ligands direct stem cell fate. Nano Lett. 15, 4720–4729 (2015).

    Article  PubMed  CAS  Google Scholar 

  69. McMurray, R. J. et al. Nanoscale surfaces for the long-term maintenance of mesenchymal stem cell phenotype and multipotency. Nat. Mater. 10, 637–644 (2011).

    Article  PubMed  CAS  Google Scholar 

  70. Park, J. S. et al. Differential effects of equiaxial and uniaxial strain on mesenchymal stem cells. Biotechnol. Bioeng. 88, 359–368 (2004).

    Article  PubMed  CAS  Google Scholar 

  71. Mauck, R. L., Byers, B. A., Yuan, X. & Tuan, R. S. Regulation of cartilaginous ECM gene transcription by chondrocytes and MSCs in 3D culture in response to dynamic loading. Biomech. Model. Mechanobiol. 6, 113–125 (2007).

    Article  PubMed  CAS  Google Scholar 

  72. Zablotskii, V. et al. Down-regulation of adipogenesis of mesenchymal stem cells by oscillating high-gradient magnetic fields and mechanical vibration. Appl. Phys. Lett. 105, 5 (2014).

    Article  CAS  Google Scholar 

  73. Guo, F. et al. Controlling cell–cell interactions using surface acoustic waves. Proc. Natl Acad. Sci. USA 112, 43–48 (2015).

    Article  PubMed  CAS  Google Scholar 

  74. Compton, J. L., Luo, J. C., Ma, H., Botvinick, E. & Venugopalan, V. High-throughput optical screening of cellular mechanotransduction. Nat. Photonics 8, 710–715 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Swift, J. et al. Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation. Science 341, 1240104 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Tajik, A. et al. Transcription upregulation via force-induced direct stretching of chromatin. Nat. Mater. 15, 1287–1296 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Tseng, P., Judy, J. W. & Di Carlo, D. Magnetic nanoparticle-mediated massively parallel mechanical modulation of single-cell behavior. Nat. Methods 9, 1113–1119 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Gossett, D. R. et al. Hydrodynamic stretching of single cells for large population mechanical phenotyping. Proc. Natl Acad. Sci. USA 109, 7630–7635 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Huh, D. et al. Reconstituting organ-level lung functions on a chip. Science 328, 1662–1668 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Fu, J. P. et al. Mechanical regulation of cell function with geometrically modulated elastomeric substrates. Nat. Methods 7, 733–736 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Weng, S., Shao, Y., Chen, W. & Fu, J. Mechanosensitive subcellular rheostasis drives emergent single-cell mechanical homeostasis. Nat. Mater. 15, 961–967 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Sutton, A. et al. Photothermally triggered actuation of hybrid materials as a new platform for in vitro cell manipulation. Nat. Commun. 8, 14700 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Kilian, K. A., Bugarija, B., Lahn, B. T. & Mrksich, M. Geometric cues for directing the differentiation of mesenchymal stem cells. Proc. Natl Acad. Sci. USA 107, 4872–4877 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. McBeath, R., Pirone, D. M., Nelson, C. M., Bhadriraju, K. & Chen, C. S. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev. Cell 6, 483–495 (2004).

    Article  PubMed  CAS  Google Scholar 

  85. Rus, D. & Tolley, M. T. Design, fabrication and control of soft robots. Nature 521, 467–475 (2015).

    Article  PubMed  CAS  Google Scholar 

  86. Pathak, M. M. et al. Stretch-activated ion channel Piezo1 directs lineage choice in human neural stem cells. Proc. Natl Acad. Sci. USA 111, 16148–16153 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Hoey, D. A., Tormey, S., Ramcharan, S., O'Brien, F. J. & Jacobs, C. R. Primary cilia-mediated mechanotransduction in human mesenchymal stem cells. Stem Cells 30, 2561–2570 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Vartiainen, M. K., Guettler, S., Larijani, B. & Treisman, R. Nuclear actin regulates dynamic subcellular localization and activity of the SRF cofactor MAL. Science 316, 1749–1752 (2007).

    Article  PubMed  CAS  Google Scholar 

  89. Connelly, J. T. et al. Actin and serum response factor transduce physical cues from the microenvironment to regulate epidermal stem cell fate decisions. Nat. Cell Biol. 12, 711–718 (2010).

    Article  PubMed  CAS  Google Scholar 

  90. Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. Pagliara, S. et al. Auxetic nuclei in embryonic stem cells exiting pluripotency. Nat. Mater. 13, 638–644 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Chen, J. C., Hoey, D. A., Chua, M., Bellon, R. & Jacobs, C. R. Mechanical signals promote osteogenic fate through a primary cilia-mediated mechanism. FASEB J. 30, 1504–1511 (2016).

    Article  PubMed  CAS  Google Scholar 

  93. Holst, J. et al. Substrate elasticity provides mechanical signals for the expansion of hemopoietic stem and progenitor cells. Nat. Biotechnol. 28, 1123–1128 (2010).

    Article  PubMed  CAS  Google Scholar 

  94. Maldonado, M. et al. The effects of electrospun substrate-mediated cell colony morphology on the self-renewal of human induced pluripotent stem cells. Biomaterials 50, 10–19 (2015).

    Article  PubMed  CAS  Google Scholar 

  95. Yahalom-Ronen, Y., Rajchman, D., Sarig, R., Geiger, B. & Tzahor, E. Reduced matrix rigidity promotes neonatal cardiomyocyte dedifferentiation, proliferation and clonal expansion. eLife 4, e07455 (2015).

    Article  PubMed Central  Google Scholar 

  96. Baker, B. M. et al. Cell-mediated fibre recruitment drives extracellular matrix mechanosensing in engineered fibrillar microenvironments. Nat. Mater. 14, 1262–1268 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Saha, S., Lin, J., De Pablo, J. J. & Palecek, S. P. Inhibition of human embryonic stem cell differentiation by mechanical strain. J. Cell. Physiol. 206, 126–137 (2006).

    Article  PubMed  CAS  Google Scholar 

  98. Zhao, C. et al. The effect of uniaxial mechanical stretch on Wnt/β-catenin pathway in bone mesenchymal stem cells. J. Craniofac. Surg. 28, 113–117 (2017).

    Article  PubMed  Google Scholar 

  99. Kinney, M. A., Saeed, R. & McDevitt, T. C. Mesenchymal morphogenesis of embryonic stem cells dynamically modulates the biophysical microtissue niche. Sci. Rep. 4, 4290 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Lü, D., Luo, C., Zhang, C., Li, Z. & Long, M. Differential regulation of morphology and stemness of mouse embryonic stem cells by substrate stiffness and topography. Biomaterials 35, 3945–3955 (2014).

    Article  PubMed  CAS  Google Scholar 

  101. Chowdhury, F. et al. Material properties of the cell dictate stress-induced spreading and differentiation in embryonic stem cells. Nat. Mater. 9, 82–88 (2010).

    Article  PubMed  CAS  Google Scholar 

  102. Vrij, E. et al. Directed assembly and development of material-free tissues with complex architectures. Adv. Mater. 28, 4032–4039 (2016).

    Article  PubMed  CAS  Google Scholar 

  103. Zoldan, J. et al. The influence of scaffold elasticity on germ layer specification of human embryonic stem cells. Biomaterials 32, 9612–9621 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Shao, Y. et al. Self-organized amniogenesis by human pluripotent stem cells in a biomimetic implantation-like niche. Nat. Mater. 16, 419–425 (2017).

    Article  PubMed  CAS  Google Scholar 

  105. Sun, Y. et al. Hippo/YAP-mediated rigidity-dependent motor neuron differentiation of human pluripotent stem cells. Nat. Mater. 13, 599–604 (2014). This study describes mechanically tuned soft substrates accelerating the differentiation of human pluripotent stem cells into functional motor neurons.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Caiazzo, M. et al. Defined three-dimensional microenvironments boost induction of pluripotency. Nat. Mater. 15, 344–352 (2016). In this study, biophysical factors in 3D microenvironments are shown to act in parallel with transcription factors to support the plasticity of somatic cells and improve reprogramming through facilitating the mesenchymal-to-epithelial transition.

    Article  PubMed  CAS  Google Scholar 

  107. Nguyen, E. H. et al. Versatile synthetic alternatives to Matrigel for vascular toxicity screening and stem cell expansion. Nat. Biomed. Eng. 1, 0096 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Aguilar, A. et al. Importance of environmental stiffness for megakaryocyte differentiation and proplatelet formation. Blood 128, 2022–2032 (2016).

    Article  PubMed  CAS  Google Scholar 

  109. Saha, K. et al. Substrate modulus directs neural stem cell behavior. Biophys. J. 95, 4426–4438 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Yang, C. et al. Spatially patterned matrix elasticity directs stem cell fate. Proc. Natl Acad. Sci. USA 113, E4439–E4445 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Tse, J. R. & Engler, A. J. Stiffness gradients mimicking in vivo tissue variation regulate mesenchymal stem cell fate. PLoS ONE 6, 9 (2011).

    Google Scholar 

  112. Sunyer, R. et al. Collective cell durotaxis emerges from long-range intercellular force transmission. Science 353, 1157–1161 (2016).

    Article  PubMed  CAS  Google Scholar 

  113. Raab, M. et al. Crawling from soft to stiff matrix polarizes the cytoskeleton and phosphoregulates myosin-II heavy chain. J. Cell Biol. 199, 669–683 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Yang, C., Tibbitt, M. W., Basta, L. & Anseth, K. S. Mechanical memory and dosing influence stem cell fate. Nat. Mater. 13, 645–652 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Li, C. X. et al. MicroRNA-21 preserves the fibrotic mechanical memory of mesenchymal stem cells. Nat. Mater. 16, 379–389 (2017).

    Article  PubMed  CAS  Google Scholar 

  116. Guvendiren, M. & Burdick, J. A. Stiffening hydrogels to probe short- and long-term cellular responses to dynamic mechanics. Nat. Commun. 3, 9 (2012).

    Article  CAS  Google Scholar 

  117. Chaudhuri, O. et al. Substrate stress relaxation regulates cell spreading. Nat. Commun. 6, 6364 (2015).

    Article  PubMed  CAS  Google Scholar 

  118. Cameron, A. R., Frith, J. E. & Cooper-White, J. J. The influence of substrate creep on mesenchymal stem cell behaviour and phenotype. Biomaterials 32, 5979–5993 (2011).

    Article  PubMed  CAS  Google Scholar 

  119. Angele, P. et al. Cyclic hydrostatic pressure enhances the chondrogenic phenotype of human mesenchymal progenitor cells differentiated in vitro. J. Orthop. Res. 21, 451–457 (2003).

    Article  PubMed  CAS  Google Scholar 

  120. Mouw, J. K., Connelly, J. T., Wilson, C. G., Michael, K. E. & Levenston, M. E. Dynamic compression regulates the expression and synthesis of chondrocyte-specific matrix molecules in bone marrow stromal cells. Stem Cells 25, 655–663 (2007).

    Article  PubMed  CAS  Google Scholar 

  121. Wang, J. et al. Mechanical stimulation orchestrates the osteogenic differentiation of human bone marrow stromal cells by regulating HDAC1. Cell Death Dis. 7, 12 (2016).

    Google Scholar 

  122. Datta, N. et al. In vitro generated extracellular matrix and fluid shear stress synergistically enhance 3D osteoblastic differentiation. Proc. Natl Acad. Sci. USA 103, 2488–2493 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Kreke, M. R., Huckle, W. R. & Goldstein, A. S. Fluid flow stimulates expression of osteopontin and bone sialoprotein by bone marrow stromal cells in a temporally dependent manner. Bone 36, 1047–1055 (2005).

    Article  PubMed  CAS  Google Scholar 

  124. Shin, J. W. et al. Contractile forces sustain and polarize hematopoiesis from stem and progenitor cells. Cell Stem Cell 14, 81–93 (2014).

    Article  PubMed  CAS  Google Scholar 

  125. Gilbert, P. M. et al. Substrate elasticity regulates skeletal muscle stem cell self-renewal in culture. Science 329, 1078–1081 (2010). In this study, substrate elasticity is shown to regulate self-renewal of skeletal muscle stem cells in vitro , which were capable of regenerating muscle tissue when transplanted in vivo.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Seib, F. P., Prewitz, M., Werner, C. & Bornhäuser, M. Matrix elasticity regulates the secretory profile of human bone marrow-derived multipotent mesenchymal stromal cells (MSCs). Biochem. Biophys. Res. Commun. 389, 663–667 (2009).

    Article  PubMed  CAS  Google Scholar 

  127. Yang, H. B., Nguyen, K. T., Leong, D. T., Tan, N. S. & Tay, C. Y. Soft material approach to induce oxidative stress in mesenchymal stem cells for functional tissue repair. ACS Appl. Mater. Interfaces 8, 26591–26599 (2016).

    Article  PubMed  CAS  Google Scholar 

  128. Lee, S. et al. Contractile force generation by 3D hiPSC-derived cardiac tissues is enhanced by rapid establishment of cellular interconnection in matrix with muscle-mimicking stiffness. Biomaterials 131, 111–120 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Huebsch, N. et al. Matrix elasticity of void-forming hydrogels controls transplanted-stem-cell-mediated bone formation. Nat. Mater. 14, 1269–1277 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Mao, A. S. et al. Deterministic encapsulation of single cells in thin tunable microgels for niche modelling and therapeutic delivery. Nat. Mater. 16, 236–243 (2017).

    Article  PubMed  CAS  Google Scholar 

  131. Darnell, M. et al. Substrate stress-relaxation regulates scaffold remodeling and bone formation in vivo. Adv. Healthc. Mater. 6, 1601185 (2017).

    Article  CAS  Google Scholar 

  132. Griffin, D. R., Weaver, W. M., Scumpia, P. O., Di Carlo, D. & Segura, T. Accelerated wound healing by injectable microporous gel scaffolds assembled from annealed building blocks. Nat. Mater. 14, 737–744 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Blaber, E. A. et al. Mechanical unloading of bone in microgravity reduces mesenchymal and hematopoietic stem cell-mediated tissue regeneration. Stem Cell Res. 13, 181–201 (2014).

    Article  PubMed  CAS  Google Scholar 

  134. Kessler, P., Neukam, F. W. & Wiltfang, J. Effects of distraction forces and frequency of distraction on bony regeneration. Br. J. Oral Maxillofac. Surg. 43, 392–398 (2005).

    Article  PubMed  CAS  Google Scholar 

  135. Cilla, M., Checa, S. & Duda, G. N. Strain shielding inspired re-design of proximal femoral stems for total hip arthroplasty. J. Orthop. Res. http://dx.doi.org/10.1002/jor.23540 (2017).

  136. Mogil, R. J. et al. Effect of low-magnitude, high-frequency mechanical stimulation on bmd among young childhood cancer survivors: a randomized clinical trial. JAMA Oncol. 2, 908–914 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Kanzaki, H., Chiba, M., Shimizu, Y. & Mitani, H. Periodontal ligament cells under mechanical stress induce osteoclastogenesis by receptor activator of nuclear factor κB ligand up-regulation via prostaglandin E-2 synthesis. J. Bone Miner. Res. 17, 210–220 (2002).

    Article  PubMed  CAS  Google Scholar 

  138. Powell, C. A., Smiley, B. L., Mills, J. & Vandenburgh, H. H. Mechanical stimulation improves tissue-engineered human skeletal muscle. Am. J. Physiol. Cell Physiol. 283, C1557–C1565 (2002). This work highlights the important role of externally applied mechanical forces in promoting the generation of tissue-engineered muscle fibres in vitro from human cells.

    Article  PubMed  CAS  Google Scholar 

  139. Moon, D. G., Christ, G., Stitzel, J. D., Atala, A. & Yoo, J. J. Cyclic mechanical preconditioning improves engineered muscle contraction. Tissue Eng. Part A 14, 473–482 (2008).

    Article  CAS  Google Scholar 

  140. Crane, J. D. et al. Massage therapy attenuates inflammatory signaling after exercise-induced muscle damage. Sci. Transl Med. 4, 119ra13 (2012).

    Article  PubMed  CAS  Google Scholar 

  141. Cezar, C. A. et al. Biologic-free mechanically induced muscle regeneration. Proc. Natl Acad. Sci. USA 113, 1534–1539 (2016). This study shows that externally applied forces alone, without growth factors or drugs, reduced fibrosis and inflammation in severely injured muscle, enhanced muscle regeneration and improved muscle function.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Celiz, A. D. et al. Discovery of a novel polymer for human pluripotent stem cell expansion and multilineage differentiation. Adv. Mater. 27, 4006–4012 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Kolesky, D. B., Homan, K. A., Skylar-Scott, M. A. & Lewis, J. A. Three-dimensional bioprinting of thick vascularized tissues. Proc. Natl Acad. Sci. USA 113, 3179–3184 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Chaudhuri, O. et al. Extracellular matrix stiffness and composition jointly regulate the induction of malignant phenotypes in mammary epithelium. Nat. Mater. 13, 970–978 (2014).

    Article  PubMed  CAS  Google Scholar 

  145. Shin, J.-W. & Mooney, D. J. Extracellular matrix stiffness causes systematic variations in proliferation and chemosensitivity in myeloid leukemias. Proc. Natl Acad. Sci. USA 113, 12126–12131 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Saxena, M. et al. EGFR and HER2 activate rigidity sensing only on rigid matrices. Nat. Mater. http://dx.doi.org/10.1038/nmat4893 (2017).

  147. Levental, I., Georges, P. C. & Janmey, P. A. Soft biological materials and their impact on cell function. Soft Matter 3, 299–306 (2007).

    Article  CAS  PubMed  Google Scholar 

  148. McDonald, S. J. et al. Early fracture callus displays smooth muscle-like viscoelastic properties ex vivo: implications for fracture healing. J. Orthop. Res. 27, 1508–1513 (2009).

    Article  PubMed  Google Scholar 

  149. Pailler-Mattei, C., Bec, S. & Zahouani, H. In vivo measurements of the elastic mechanical properties of human skin by indentation tests. Med. Eng. Phys. 30, 599–606 (2008).

    Article  PubMed  CAS  Google Scholar 

  150. Discher, D. E., Mooney, D. J. & Zandstra, P. W. Growth factors, matrices, and forces combine and control stem cells. Science 324, 1673–1677 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Jansen, L. E., Birch, N. P., Schiffman, J. D., Crosby, A. J. & Peyton, S. R. Mechanics of intact bone marrow. J. Mech. Behav. Biomed. Mater. 50, 299–307 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Follet, H., Boivin, G., Rumelhart, C. & Meunier, P. J. The degree of mineralization is a determinant of bone strength: a study on human calcanei. Bone 34, 783–789 (2004).

    Article  PubMed  CAS  Google Scholar 

  153. Zhang, Y.-R., Du, W., Zhou, X.-D. & Yu, H.-Y. Review of research on the mechanical properties of the human tooth. Int. J. Oral Sci. 6, 61–69 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Wozniak, M. A. & Chen, C. S. Mechanotransduction in development: a growing role for contractility. Nat. Rev. Mol. Cell Biol. 10, 34–43 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Nam, S., Hu, K. H., Butte, M. J. & Chaudhuri, O. Strain-enhanced stress relaxation impacts nonlinear elasticity in collagen gels. Proc. Natl Acad. Sci. USA 113, 5492–5497 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Loy, C., Laine, A. & Mantovani, D. Rotation-based technique for the rapid densification of tubular collagen gel scaffolds. Biotechnol. J. 11, 1673–1679 (2016).

    Article  PubMed  CAS  Google Scholar 

  157. Hu, M. et al. A biomimetic gelatin-based platform elicits a pro-differentiation effect on podocytes through mechanotransduction. Sci. Rep. 7, 43934 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Trichet, L. et al. Evidence of a large-scale mechanosensing mechanism for cellular adaptation to substrate stiffness. Proc. Natl Acad. Sci. USA 109, 6933–6938 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Azzolin, L. et al. YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response. Cell 158, 157–170 (2014).

    Article  PubMed  CAS  Google Scholar 

  160. Makarenkova, H. P. et al. Differential interactions of FGFs with heparan sulfate control gradient formation and branching morphogenesis. Sci. Signal. 2, ra55 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank J. Li for assistance with revising this manuscript and D. Zhang for input on the figures. Funding was provided by the National Institute of Dental and Craniofacial Research of the US National Institutes of Health (NIH) under Award Numbers 5R01DE013033 (D.M.) and K08DE025292 (K.H.V.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Author information

Authors and Affiliations

  1. Wyss Institute for Biologically Inspired Engineering and John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, 02138, Massachusetts, USA

    Kyle H. Vining & David J. Mooney

Authors
  1. Kyle H. Vining
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David J. Mooney
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.H.V. and D.J.M. researched data for the article, contributed to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to David J. Mooney.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (table)

Mechanical cues guide development processes (PDF 104 kb)

Supplementary information S2 (box)

Techniques to apply and measure extrinsic forces on cells (PDF 97 kb)

Supplementary information S3 (table)

Stem cells respond diversely to forces in models of mechanobiology (PDF 128 kb)

PowerPoint slides

Glossary

Cadherin–catenin complexes

Complexes of cellular receptors termed cadherins, which bind to other cells, with β-catenin, an intracellular molecule, that connect to the actin cytoskeleton in epithelial tissues to convey forces between cells.

Dorsal closure

Closure of a dorsal epidermal opening that is initially formed naturally during embryonic development of Drosophila melanogaster; this process has similarities to wound healing in mammals.

Cortical tension

A type of cytoskeletal tension caused by actomyosin-generated forces; it contributes to cell shape and mechanical properties.

RHO-associated protein kinase

(ROCK). A serine/threonine kinase that can regulate actomyosin contractility and is downstream of RHOA and other pathways.

Stomodeum

A frontal opening in the developing embryo that forms a primordial mouth, separated from the pharynx by an oropharyngeal membrane.

Traction forces

Forces on extracellular matrix or other cells generated by receptor binding and actomyosin contractility.

Fractal patterns

Highly branched geometric patterns that are formed from repeated symmetrical branching, often across multiple length scales.

Submandibular salivary gland

One of the major salivary glands, it features a branched ductal structure that opens into the oral cavity, with secretory end pieces called acini that produce saliva by secretion of water, salts, proteins and other macromolecules.

Focal adhesions

Large and dynamic protein complexes of matrix receptors, actin cytoskeleton and other cytoskeletal and signalling molecules that link the cytoskeleton to the extracellular matrix.

Isometric muscle contraction

A type of force generated by muscle while maintaining constant muscle length and joint angle.

Convective flow

Fluid flow that transfers mass and/or heat down a fluid pressure gradient.

Microfluidics

The precise control of fluid shear forces and flow rates in micro-scale geometries, such as micro-channels.

Substrate creep

The deformation, or flow, of a material during a constant application of stress.

Stress stiffening

The mechanical stiffening of a polymer network with increasing strain.

Sarcomere

A fundamental active unit in skeletal muscle that generates force from overlapping striations of actin and myosin.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vining, K., Mooney, D. Mechanical forces direct stem cell behaviour in development and regeneration. Nat Rev Mol Cell Biol 18, 728–742 (2017). https://doi.org/10.1038/nrm.2017.108

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm.2017.108

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research