Extracellular-matrix tethering regulates stem-cell fate
Source abstract
Abstract
To investigate how substrate properties influence stem-cell fate, we cultured single human epidermal stem cells on polydimethylsiloxane (PDMS) and polyacrylamide (PAAm) hydrogel surfaces, 0.1 kPa-2.3 MPa in stiffness, with a covalently attached collagen coating. Cell spreading and differentiation were unaffected by polydimethylsiloxane stiffness. However, cells on polyacrylamide of low elastic modulus (0.5 kPa) could not form stable focal adhesions and differentiated as a result of decreased activation of the extracellular-signal-related kinase (ERK)/mitogen-activated protein kinase (MAPK) signalling pathway. The differentiation of human mesenchymal stem cells was also unaffected by PDMS stiffness but regulated by the elastic modulus of PAAm. Dextran penetration measurements indicated that polyacrylamide substrates of low elastic modulus were more porous than stiff substrates, suggesting that the collagen anchoring points would be further apart. We then changed collagen crosslink concentration and used hydrogel-nanoparticle substrates to vary anchoring distance at constant substrate stiffness. Lower collagen anchoring density resulted in increased differentiation. We conclude that stem cells exert a mechanical force on collagen fibres and gauge the feedback to make cell-fate decisions.
Source: europepmc · Quality: candidate unverified · Source record ↗
Research context
OpenAlex topics: Cellular Mechanics and Interactions · 3D Printing in Biomedical Research · Bone Tissue Engineering Materials
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
References (35)
Show source-provided references
1. Watt, F. M. & Hogan, B. L. M. Out of Eden: Stem cells and their niches. Science 287, 1427–1430 (2000).10.1126/science.287.5457.1427 ↗
2. Pelham, R. J. & Wang, Y. Cell locomotion and focal adhesions are regulated by substrate flexibility. Proc. Natl Acad. Sci. USA 94, 13661–13665 (1997).10.1073/pnas.94.25.13661 ↗
3. Engler, A. J., Sen, S., Sweeney, H. L. & Discher, D. E. Matrix elasticity directs stem cell lineage specification. Cell 126, 677–689 (2006).10.1016/j.cell.2006.06.044 ↗
4. Chen, C. S., Mrksich, M., Huang, S., Whitesides, G. M. & Ingber, D. E. Geometric control of cell life and death. Science 276, 1425–1428 (1997).10.1126/science.276.5317.1425 ↗
5. 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).10.1016/S1534-5807(04)00075-9 ↗
6. Watt, F. M., Jordan, P. W. & O’Neill, C. H. Cell-shape controls terminal differentiation of human epidermal keratinocytes. Proc. Natl Acad. Sci. USA 85, 5576–5580 (1988).10.1073/pnas.85.15.5576 ↗
7. Selhuber-Unkel, C. et al. Cell adhesion strength is controlled by intermolecular spacing of adhesion receptors. Biophys. J. 98, 543–551 (2010).10.1016/j.bpj.2009.11.001 ↗
8. Discher, D. E., Janmey, P. & Wang, Y. Tissue cells feel and respond to the stiffness of their substrate. Science 310, 1139–1143 (2005).10.1126/science.1116995 ↗
9. Prager-Khoutorsky, M. et al. Fibroblast polarization is a matrix-rigidity-dependent process controlled by focal adhesion mechanosensing. Nature Cell Biol. 13, 1457–1465 (2011).10.1038/ncb2370 ↗
10. Watt, F. M. Terminal differentiation of human keratinocytes. Curr. Opin.Cell Biol. 1, 1107–1115 (1989).10.1016/S0955-0674(89)80058-4 ↗
11. Adams, J. C. & Watt, F. M. Fibronectin inhibits the terminal differentiation of human keratinocytes. Nature 340, 307–309 (1989).10.1038/340307a0 ↗
12. Connelly, J. T. et al. Actin and serum response factor transduce physical cues from the microenvironment to regulate epidermal stem cell fate decisions. Nature Cell Biol. 12, 711–718 (2010).10.1038/ncb2074 ↗
13. Yim, E. K. F. et al. Nanopattern-induced changes in morphology and motility of smooth muscle cells. Biomaterials 26, 5405–5413 (2005).10.1016/j.biomaterials.2005.01.058 ↗
14. Murrell, M., Kamm, R. D. & Matsudaira, P. T. Substrate viscosity enhances correlation in epithelial cell motion. Biophys. J. 101, 297–306 (2011).10.1016/j.bpj.2011.05.048 ↗
15. Gray, D. S., Tien, J. & Chen, C. S. Repositioning of cells by mechanotaxis on surfaces with micropatterned Young’s modulus. J. Biomed. Mater. Res. 66A, 605–614 (2003).10.1002/jbm.a.10585 ↗
16. Galli, M., Comley, K. S. C., Shean, T. A. V. & Oyen, M. L. Viscoelastic and poroelastic mechanical characterization of hydrated gels. J. Mater. Res. 24, 973–979 (2009).10.1557/jmr.2009.0129 ↗
17. Yeung, T. et al. Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion. Cell Motil. Cytoskelton 60, 24–34 (2005).10.1002/cm.20041 ↗
18. Chung, K. H. et al. Nanomechanical properties of thin films of type I collagen fibrils. Langmuir 26, 3629–3636 (2010).10.1021/la903073v ↗
19. Ezhkova, E. et al. Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell 136, 1122–1135 (2009).10.1016/j.cell.2008.12.043 ↗
20. Zhu, A. J., Haase, I. & Watt, F. M. Signaling via beta 1 integrins and mitogen-activated protein kinase determines human epidermal stem cell fate in vitro. Proc. Natl Acad. Sci. USA 96, 6728–6733 (1999).10.1073/pnas.96.12.6728 ↗
21. Evans, R. D. et al. A tumor-associated beta 1 integrin mutation that abrogates epithelial differentiation control. J. Cell Biol. 160, 589–596 (2003).10.1083/jcb.200209016 ↗
22. Paumelle, R. et al. Sequential activation of ERK and repression of JNK by scatter factor/hepatocyte growth factor in Madin-Darby canine kidney epithelial cells. Mol. Biol. Cell 11, 3751–3763 (2000).10.1091/mbc.11.11.3751 ↗
23. Little, W. C., Smith, M. L., Ebneter, U. & Vogel, V. Assay to mechanically tune and optically probe fibrillar fibronectin conformations from fully relaxed to breakage. Matrix Biol. 27, 451–461 (2008).10.1016/j.matbio.2008.02.003 ↗
24. Antia, M., Baneyx, G., Kubow, K. E. & Vogel, V. Fibronectin in aging extracellular matrix fibrils is progressively unfolded by cells and elicits and enhanced rigidity response. Faraday Discuss. 139, 229–249 (2008).10.1039/b718714a ↗
25. Strange, D. G. T. & Oyen, M. L. Composite hydrogels for nucleus pulposus tissue engineering. J. Mech. Behav. Biomed. Mater.http://dx.doi.org/10.1016/j.jmbbm.2011.10.003 (2011).10.1016/j.jmbbm.2011.10.003 ↗
26. Hu, Y., Zhao, X., Vlassak, J. J. & Suo, Z. Using indentation to characterize the poroelasticity of gels. Appl. Phys. Lett. 96, 121904 (2010).10.1063/1.3370354 ↗
27. Weiss, N., van Vliet, T. & Silberberg, A. Permeability of heterogeneous gels. J. Polym. Sci. 17, 2229–2240 (1979).
28. Huebsch, N. et al. Harnessing traction-mediated manipulation of the cell/matrix interface to control stem-cell fate. Nature Mater. 9, 518–526 (2010).10.1038/nmat2732 ↗
29. Storm, C. et al. Nonlinear elasticity in biological gels. Nature 435, 191–194 (2005).10.1038/nature03521 ↗
30. Gere, J. M. & Goodno, B. J. Mechanics of Materials 7th edn (Cengage Learning, 2009).
31. Choquet, D., Felsenfeld, D. P. & Sheetz, M. P. Extracellular matrixrigidity causes strengthening of integrin–cytoskeleton linkages. Cell 88, 39–48 (1997).10.1016/S0092-8674(00)81856-5 ↗
32. Aydin, D. et al. Polymeric substrates with tunable elasticity and nanoscopically controlled biomolecule presentation. Langmuir 26, 15472–15480 (2010).10.1021/la103065x ↗
33. Aydin, D., Hirschfeld-Warneken, V. C., Louban, I. & Spatz, J. P. Intelligent induction of active biosystem responses at interfaces. Int. J. Mater. Res. 102, 796–808 (2011).10.3139/146.110531 ↗
34. Watt, F. M., Broad, S. M. & Prowse, D. M. in Cell Biology. A Laboratory Handbook 3rd edn, Vol. 1 (ed. Celis, J.E.) Ch. 16, 133–138 (Elsevier, 2005).
35. Warley, A. & Skepper, J. N. Evidence against movement of ions during freeze-drying of thin sections of biological material for X-ray microanalysis. J. Microsc. 196, 116–123 (2000).10.1046/j.1365-2818.2000.00693.x ↗