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Mechanical memory and dosing influence stem cell fate

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.

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Figure 1: Mechanical dosing and memory of hMSCs.
Figure 2: Influence of phototunable substrate modulus on YAP and RUNX2 activation.
Figure 3: Reversible and irreversible effects of mechanical dosing on phototunable hydrogels.
Figure 4: Influence of mechanical dosing on differentiation of hMSCs.

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Acknowledgements

This work was supported by the National Science Foundation (DMR 1006711; K.S.A.), the National Institutes of Health (1R21 AR057904, R01 DE016523), the Howard Hughes Medical Institute (K.S.A.), the Teets Family Endowed Doctoral Fellowship (M.W.T.), and the Molecular Biophysics Training Grant from the National Institutes of Health (T32 GM-065103; M.W.T.). We would like to thank R. Tjian and I. Grubisic for helpful discussions on the work as well as E. A. Appel and T. A. Tauer for advice on figure preparation.

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M.W.T., C.Y. and K.S.A. conceived the ideas and designed the experiments. C.Y., L.B. and M.W.T. conducted the experiments and analysed the data. M.W.T., C.Y., L.B. and K.S.A. interpreted the data and wrote the manuscript.

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Yang, C., Tibbitt, M., Basta, L. et al. Mechanical memory and dosing influence stem cell fate. Nature Mater 13, 645–652 (2014). https://doi.org/10.1038/nmat3889

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