title: 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.
authors.affiliation: 1] Department of Chemistry and Biochemistry, University of Colorado Boulder, 3415 Colorado Avenue, Boulder, Colorado 80303, USA [2].
authors.forename: Chun
authors.initials: C
authors.lastname: Yang
authors.affiliation: 1] Department of Chemical and Biological Engineering, University of Colorado Boulder, 3415 Colorado Avenue, Boulder, Colorado 80303, USA [2] [3].
authors.forename: Mark W
authors.initials: MW
authors.lastname: Tibbitt
authors.affiliation: Department of Chemical and Biological Engineering, University of Colorado Boulder, 3415 Colorado Avenue, Boulder, Colorado 80303, USA.
authors.forename: Lena
authors.initials: L
authors.lastname: Basta
authors.affiliation: 1] Department of Chemical and Biological Engineering, University of Colorado Boulder, 3415 Colorado Avenue, Boulder, Colorado 80303, USA [2] Howard Hughes Medical Institute, University of Colorado Boulder, 3415 Colorado Avenue, Boulder, Colorado 80303, USA [3] BioFrontiers Institute, University of Colorado Boulder, 3415 Colorado Avenue, Boulder, Colorado 80303, USA.
authors.forename: Kristi S
authors.initials: KS
authors.lastname: Anseth
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002454:Cell Differentiation; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D006801:Humans; D020100:Hydrogels / Q000737:chemistry*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis; D010750:Phosphoproteins / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry*; D014157:Transcription Factors / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050659:Core Binding Factor Alpha 1 Subunit; D020100:Hydrogels; D010750:Phosphoproteins; C493709:RUNX2 protein, human; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D011092:Polyethylene Glycols; D000217:Acyltransferases; C108675:TAFAZZIN protein, human