Stress-stiffening-mediated stem-cell commitment switch in soft responsive hydrogels

Nat Mater. 2016 Mar;15(3):318-25. doi: 10.1038/nmat4483. Epub 2015 Nov 30.


Bulk matrix stiffness has emerged as a key mechanical cue in stem cell differentiation. Here, we show that the commitment and differentiation of human mesenchymal stem cells encapsulated in physiologically soft (∼0.2-0.4 kPa), fully synthetic polyisocyanopeptide-based three-dimensional (3D) matrices that mimic the stiffness of adult stem cell niches and show biopolymer-like stress stiffening, can be readily switched from adipogenesis to osteogenesis by changing only the onset of stress stiffening. This mechanical behaviour can be tuned by simply altering the material's polymer length whilst maintaining stiffness and ligand density. Our findings introduce stress stiffening as an important parameter that governs stem cell fate in a 3D microenvironment, and reveal a correlation between the onset of stiffening and the expression of the microtubule-associated protein DCAMKL1, thus implicating DCAMKL1 in a stress-stiffening-mediated, mechanotransduction pathway that involves microtubule dynamics in stem cell osteogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biocompatible Materials
  • Biomechanical Phenomena
  • Cell Culture Techniques
  • Cell Differentiation
  • Gene Expression Regulation / physiology
  • Humans
  • Hydrogels*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Materials Testing
  • Mesenchymal Stem Cells / physiology*
  • Molecular Structure
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Stress, Mechanical*


  • Biocompatible Materials
  • Hydrogels
  • Intracellular Signaling Peptides and Proteins
  • DCLK1 protein, human
  • Protein-Serine-Threonine Kinases