Hepatic stellate cells require a stiff environment for myofibroblastic differentiation

Abby L. Olsen, Steven A. Bloomer, Erick P. Chan, Marianna D.A. Gaça, Penelope C. Georges, Bridget Sackey, Masayuki Uemura, Paul A. Janmey, Rebecca G. Wells

Research output: Contribution to journalArticlepeer-review

204 Scopus citations

Abstract

The myofibroblastic differentiation of hepatic stellate cells (HSC) is a critical event in liver fibrosis and is part of the final common pathway to cirrhosis in chronic liver disease from all causes. The molecular mechanisms driving HSC differentiation are not fully understood. Because macroscopic tissue stiffening is a feature of fibrotic disease, we hypothesized that mechanical properties of the underlying matrix are a principal determinant of HSC activation. Primary rat HSC were cultured on inert polyacrylamide supports of variable but precisely defined shear modulus (stiffness) coated with different extracellular matrix proteins or poly-L-lysine. HSC differentiation was determined by cell morphology, immunofluorescence staining, and gene expression. HSC became progressively myofibroblastic as substrate stiffness increased on all coating matrices, including Matrigel. The degree rather than speed of HSC activation correlated with substrate stiffness, with cells cultured on supports of intermediate stiffness adopting stable intermediate phenotypes. Quiescent cells on soft supports were able to undergo myofibroblastic differentiation with exposure to stiff supports. Stiffness-dependent differentiation required adhesion to matrix proteins and the generation of mechanical tension. Transforming growth factor-β treatment enhanced differentiation on stiff supports, but was not required. HSC differentiate to myofibroblasts in vitro primarily as a function of the physical rather than the chemical properties of the substrate. HSC require a mechanically stiff substrate, with adhesion to matrix proteins and the generation of mechanical tension, to differentiate. These findings suggest that alterations in liver stiffness are a key factor driving the progression of fibrosis.

Original languageEnglish (US)
Pages (from-to)G110-G118
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume301
Issue number1
DOIs
StatePublished - Jul 2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Keywords

  • Liver fibrosis
  • Matrigel
  • Matrix stiffness
  • Myofibroblast
  • Transforming growth factor-β

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