1] Department of Chemistry and Biochemistry, University of Colorado Boulder, 3415 Colorado Avenue, Boulder, Colorado 80303, USA [2].
1] Department of Chemical and Biological Engineering, University of Colorado Boulder, 3415 Colorado Avenue, Boulder, Colorado 80303, USA [2] [3].
Nat Mater. 2014 Jun;13(6):645-52. doi: 10.1038/nmat3889. Epub 2014 Mar 16.
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.
我们研究了干细胞是否能记住过去的物理信号，以及是否可以利用这些信号来机械地给细胞加药。我们发现，在软聚乙二醇（PEG）水凝胶（杨氏模量 E2kPa）上培养的人骨髓间充质干细胞（hMSCs）中，Yes 相关蛋白（YAP）和含 PDZ 结合域的转录共激活因子（TAZ）以及预成骨转录因子 RUNX2 的激活取决于之前在硬细胞培养聚苯乙烯（TCPS；E3GPa）上的培养时间。此外，对最初在硬（E10kPa）然后软（E2kPa）的光可调 PEG 水凝胶上培养的 hMSCs 进行机械加药，会导致 YAP/TAZ 和 RUNX2 的激活是可逆的，或者超过机械剂量阈值时是不可逆的。我们还发现，在超高生理硬度的 TCPS 上增加机械加药会促使 hMSCs 向成骨分化。我们的结论是，干细胞具有机械记忆——YAP/TAZ 作为细胞内的机械变阻器——可以存储来自过去物理环境的信息，并影响细胞的命运。
