Degradation-mediated cellular traction directs stem cell fate in covalently crosslinked three-dimensional hydrogels

Nat Mater. 2013 May;12(5):458-65. doi: 10.1038/nmat3586. Epub 2013 Mar 24.


Although cell-matrix adhesive interactions are known to regulate stem cell differentiation, the underlying mechanisms, in particular for direct three-dimensional encapsulation within hydrogels, are poorly understood. Here, we demonstrate that in covalently crosslinked hyaluronic acid (HA) hydrogels, the differentiation of human mesenchymal stem cells (hMSCs) is directed by the generation of degradation-mediated cellular traction, independently of cell morphology or matrix mechanics. hMSCs within HA hydrogels of equivalent elastic moduli that permit (restrict) cell-mediated degradation exhibited high (low) degrees of cell spreading and high (low) tractions, and favoured osteogenesis (adipogenesis). Moreover, switching the permissive hydrogel to a restrictive state through delayed secondary crosslinking reduced further hydrogel degradation, suppressed traction, and caused a switch from osteogenesis to adipogenesis in the absence of changes to the extended cellular morphology. Furthermore, inhibiting tension-mediated signalling in the permissive environment mirrored the effects of delayed secondary crosslinking, whereas upregulating tension induced osteogenesis even in the restrictive environment.

Publication types

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

MeSH terms

  • Cell Differentiation / drug effects*
  • Humans
  • Hyaluronic Acid / chemistry
  • Hyaluronic Acid / metabolism*
  • Hyaluronic Acid / pharmacology*
  • Hydrogels / chemistry
  • Hydrogels / metabolism*
  • Hydrogels / pharmacology*
  • Mesenchymal Stem Cells / cytology*
  • Mesenchymal Stem Cells / drug effects*
  • Osteogenesis / drug effects
  • Proteolysis


  • Hydrogels
  • Hyaluronic Acid