Mechanical memory and dosing influence stem cell fate
Source abstract
Abstract
We investigated whether stem cells remember past physical signals and whether these can be exploited to dose cells mechanically. We found that the activation of the Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding domain (TAZ) as well as the pre-osteogenic transcription factor RUNX2 in human mesenchymal stem cells (hMSCs) cultured on soft poly(ethylene glycol) (PEG) hydrogels (Young's modulus E ~ 2 kPa) depended on previous culture time on stiff tissue culture polystyrene (TCPS; E ~ 3 GPa). In addition, mechanical dosing of hMSCs cultured on initially stiff (E ~ 10 kPa) and then soft (E ~ 2 kPa) phototunable PEG hydrogels resulted in either reversible or--above a threshold mechanical dose--irreversible activation of YAP/TAZ and RUNX2. We also found that increased mechanical dosing on supraphysiologically stiff TCPS biases hMSCs towards osteogenic differentiation. We conclude that stem cells possess mechanical memory--with YAP/TAZ acting as an intracellular mechanical rheostat--that stores information from past physical environments and influences the cells' fate.
Source: europepmc · Quality: candidate unverified · Source record ↗
Research context
OpenAlex topics: Cellular Mechanics and Interactions · Hippo pathway signaling and YAP/TAZ · Pluripotent Stem Cells Research
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
References (31)
Show source-provided references
1. Pelham, R. J. & Wang, Y. L. 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 ↗
2. 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 ↗
3. 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).10.1073/pnas.0903269107 ↗
4. McMurray, R. J. et al. Nanoscale surfaces for the long-term maintenance of mesenchymal stem cell phenotype and multipotency. Nature Mater. 10, 637–644 (2011).10.1038/nmat3058 ↗
5. Guvendiren, M. & Burdick, J. A. Stiffening hydrogels to probe short- and long-term cellular responses to dynamic mechanics. Nature Commun. 3, 792 (2012).10.1038/ncomms1792 ↗
6. Trappmann, B. et al. Extracellular-matrix tethering regulates stem-cell fate. Nature Mater. 11, 642–649 (2012).10.1038/nmat3339 ↗
7. Khetan, S. et al. Degradation-mediated cellular traction directs stem cell fate in covalently crosslinked three-dimensional hydrogels. Nature Mater. 12, 458–465 (2013).10.1038/nmat3586 ↗
8. 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 ↗
9. Discher, D. E., Mooney, D. J. & Zandstra, P. W. Growth factors, matrices, and forces combine and control stem cells. Science 324, 1673–1677 (2009).10.1126/science.1171643 ↗
10. Guilak, F. et al. Control of stem cell fate by physical interactions with the extracellular matrix. Cell Stem Cell 5, 17–26 (2009).10.1016/j.stem.2009.06.016 ↗
11. 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 ↗
12. Ingber, D. E. Fibronectin controls capillary endothelial-cell growth by modulating cell shape. Proc. Natl Acad. Sci. USA 87, 3579–3583 (1990).10.1073/pnas.87.9.3579 ↗
13. 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 ↗
14. Gilbert, P. M. et al. Substrate elasticity regulates skeletal muscle stem cell self-renewal in culture. Science 329, 1078–1081 (2010).10.1126/science.1191035 ↗
15. Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011).10.1038/nature10137 ↗
16. Halder, G., Dupont, S. & Piccolo, S. Transduction of mechanical and cytoskeletal cues by YAP and TAZ. Nat. Rev. Mol. Cell Biol. 13, 591–600 (2012).10.1038/nrm3416 ↗
17. Maloney, J. M. et al. Mesenchymal stem cell mechanics from the attached to the suspended state. Biophys. J. 99, 2479–2487 (2010).10.1016/j.bpj.2010.08.052 ↗
18. Kloxin, A. M., Kasko, A. M., Salinas, C. N. & Anseth, K. S. Photodegradable hydrogels for dynamic tuning of physical and chemical properties. Science 324, 59–63 (2009).10.1126/science.1169494 ↗
19. Kloxin, A. M., Tibbitt, M. W. & Anseth, K. S. Synthesis of photodegradable hydrogels as dynamically tunable cell culture platforms. Nature Protocols 5, 1867–1887 (2010).10.1038/nprot.2010.139 ↗
20. Kloxin, A. M., Tibbitt, M. W., Kasko, A. M., Fairbairn, J. F. & Anseth, K. S. Tunable hydrogels for external manipulation of cellular microenvironments through controlled photodegradation. Adv. Mater. 22, 61–66 (2010).10.1002/adma.200900917 ↗
21. Tibbitt, M. W., Kloxin, A. M. & Anseth, K. S. Modeling controlled photodegradation in optically thick hydrogels. J. Polym. Sci. Pol. Chem. 51, 1899–1911 (2013).10.1002/pola.26574 ↗
22. Tibbitt, M. W., Kloxin, A. M., Sawicki, L. A. & Anseth, K. S. Mechanical properties and degradation of chain and step-polymerized photodegradable hydrogels. Macromolecules 46, 2785–2792 (2013).10.1021/ma302522x ↗
23. Wong, D. Y., Griffin, D. R., Reed, J. & Kasko, A. M. Photodegradable hydrogels to generate positive and negative features over multiple length scales. Macromolecules 43, 2824–2831 (2010).10.1021/ma9023679 ↗
24. Kloxin, A. M., Benton, J. A. & Anseth, K. S. In situ elasticity modulation with dynamic substrates to direct cell phenotype. Biomaterials 31, 1–8 (2010).10.1016/j.biomaterials.2009.09.025 ↗
25. Tibbitt, M. W., Kloxin, A. M., Dyamenahalli, K. U. & Anseth, K. S. Controlled two-photon photodegradation of PEG hydrogels to study and manipulate subcellular interactions on soft materials. Soft Matter 6, 5100–5108 (2010).10.1039/c0sm00174k ↗
26. Wang, H., Haeger, S. M., Kloxin, A. M., Leinwand, L. A. & Anseth, K. S. Redirecting valvular myofibroblasts into dormant fibroblasts through light-mediated reduction in substrate modulus. PloS ONE 7, e39969 (2012).10.1371/journal.pone.0039969 ↗
27. Frey, M. T. & Wang, Y. L. A photo-modulatable material for probing cellular responses to substrate rigidity. Soft Matter 5, 1918–1924 (2009).10.1039/b818104g ↗
28. Wang, H., Tibbitt, M. W., Langer, S. J., Leinwand, L. A. & Anseth, K. S. Hydrogels preserve native phenotypes of valvular fibroblasts through an elasticity-regulated pi3k/akt pathway. Proc. Natl Acad. Sci. USA 110, 19336–19341 (2013).10.1073/pnas.1306369110 ↗
29. Pittenger, M. F. et al. Multilineage potential of adult human mesenchymal stem cells. Science 284, 143–147 (1999).10.1126/science.284.5411.143 ↗
30. Shin, J. W. et al. Mechanobiology of bone marrow stem cells: From myosin-II forces to compliance of matrix and nucleus in cell forms and fates. Differentiation 86, 77–86 (2013).10.1016/j.diff.2013.05.001 ↗
31. Mariner, P. D., Johannesen, E. & Anseth, K. S. Manipulation of miRNA activity accelerates osteogenic differentiation of hMSCs in engineered 3d scaffolds. J. Tissue Eng. Regen. Med. 6, 314–324 (2012).10.1002/term.435 ↗