Mechanical Memory and Dosing Influence Stem Cell Fate

Nat Mater. 2014 Jun;13(6):645-52. doi: 10.1038/nmat3889. Epub 2014 Mar 16.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Cell Differentiation*
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Humans
  • Hydrogels / chemistry*
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism*
  • Osteogenesis*
  • Phosphoproteins / metabolism
  • Polyethylene Glycols / chemistry*
  • Transcription Factors / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Core Binding Factor Alpha 1 Subunit
  • Hydrogels
  • Phosphoproteins
  • RUNX2 protein, human
  • TAZ protein, human
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • Polyethylene Glycols