The mechanical memory of lung myofibroblasts
Top Cited Papers
- 1 January 2012
- journal article
- Published by Oxford University Press (OUP) in Integrative Biology
- Vol. 4 (4), 410-421
- https://doi.org/10.1039/c2ib00149g
Abstract
Fibroblasts differentiate into the highly synthetic and contractile myofibroblast phenotype when exposed to substrates with an elastic modulus corresponding to pathologically stiff fibrotic tissue. Cellular responses to changes in substrate stiffness are typically analyzed after hours or days, which does not enable the monitoring of myofibroblast persistence, a hallmark of fibrosis. To determine long-lasting effects on the fibrotic behavior of lung fibroblasts, we followed a novel approach of explanting and repeatedly passaging fibroblasts on silicone substrates with stiffness representing various states of lung health. Fibrotic activity was determined by assaying for myofibroblast proliferation, cell contractility, expression of α-smooth muscle actin, extracellular matrix and active TGFβ1. As predicted, myofibroblast activity was low on healthy soft substrates and increased with increasing substrate stiffness. However, explanting and mechanically priming lung fibroblasts for 3 weeks on pathologically stiff substrates resulted in sustained myofibroblast activity even after the cells were returned to healthy soft cultures for 2 weeks. Such primed cells retained higher fibrotic activity than cells that had been exclusively cultured on soft substrates, and were not statistically different from cells continuously passaged on stiff surfaces. Inversely, priming lung fibroblasts for 3 weeks on soft substrates partially protected from myofibroblast activation after the shift to stiff substrates. Hence, mechano-sensed information relating to physical conditions of the local cellular environment could permanently induce fibrotic behavior of lung fibroblasts. This priming effect has important implications for the progression and persistence of aggressive fibrotic diseases such as idiopathic pulmonary fibrosis.Keywords
This publication has 68 references indexed in Scilit:
- Myocardin-Related Transcription Factors A and B Are Key Regulators of TGF-β1-Induced Fibroblast to Myofibroblast DifferentiationJournal of Investigative Dermatology, 2011
- The effect of matrix stiffness on the differentiation of mesenchymal stem cells in response to TGF-βBiomaterials, 2011
- Microelastic properties of lung cell-derived extracellular matrixActa Biomaterialia, 2011
- Epigenetics in Alternative Pre-mRNA SplicingCell, 2011
- Mechanical Forces Regulate Elastase Activity and Binding Site Availability in Lung ElastinBiophysical Journal, 2010
- Methylation determines fibroblast activation and fibrogenesis in the kidneyNature Medicine, 2010
- Boundary Stiffness Regulates Fibroblast Behavior in Collagen GelsAnnals of Biomedical Engineering, 2009
- Cell-Cycle Control by Physiological Matrix Elasticity and In Vivo Tissue StiffeningCurrent Biology, 2009
- Epigenetic reprogramming during wound healing: loss of polycomb‐mediated silencing may enable upregulation of repair genesEMBO Reports, 2009
- The hard life of soft cellsCell Motility, 2009