RESEARCH HIGHLIGHTS Nature Reviews Molecular Cell Biology | AOP, published online 12 November 2014; doi:10.1038/nrm3906
E X T R A C E L L U L A R M AT R I X
Preconditioning the ECM for fibrosis differences in ECM structure might affect contractioninduced TGFβ1 activation Sagittal section of a mechanically restrained rat skin wound showing that activation of myofibroblasts (α-smooth muscle actin, blue) associates with high fibrillar organization of fibronectin (red) and LTBP1 (green). Image courtesy of Boris Hinz, University of Toronto, Canada.
Remodelling of the extracellular matrix (ECM) by myofibroblasts is crucial for wound repair, but if dysregulated can result in pathological fibrosis. Hinz and colleagues describe how pre-organization of the ECM by myofibroblasts can prime for increased fibrosis by regulating the activation of the pro-fibrotic cytokine transforming growth factor-β (TGFβ). Latent TGFβ is secreted bound to latency-associated peptide (LAP), which binds to the ECM protein latent TGFβ-binding protein 1 (LTBP1). Integrin-dependent binding of contracting myofibroblasts to LAP induces a conformational change in LAP that releases active
TGFβ from the ECM. Therefore, the short-term contractile state of the wound determines the activity of TGFβ. New work now shows that this process is augmented by longerterm changes to the organization of the ECM. In a rat model of wound healing, restraining the wound edges mechanically resulted in accelerated expression of ECM proteins such as fibronectin and LTBP1, and increased fibril organization of the ECM, which correlated with increased TGFβ1 signalling. This increased ECM organization was the result of increased strain exerted by myofibroblasts. Highcontractile human dermal myo fibroblasts (DMFs) had increased expression of ECM proteins compared with low-contractile human dermal fibroblasts (DFs), and there was greater organization of LTBP1 and fibronectin in the DMF ECM than in the DF ECM. Moreover, cell contraction resulted in threefold higher levels of active TGFβ1 in human DMF cultures compared with human DF cultures. This indicates that differences in ECM structure might affect contractioninduced TGFβ1 activation. In support of this, when decellularized ECM from human DMFs and from human DFs was reseeded with human DMFs, DMF contraction-induced activation of TGFβ1 was twofold greater from DMF-remodelled ECM than from
NATURE REVIEWS | MOLECULAR CELL BIOLOGY
DF-remodelled ECM, despite similar total levels of TGFβ1. This correlated with the extent of ECM organization, which was significantly higher in DMF cultures than in DF cultures. The authors confirmed that preorganization of the ECM affects TGFβ1 activation using Fak–/– mouse embryonic fibroblasts, which have a disorganized ECM with a low fibril density and are defective for TGFβ activation. Increasing the pre-strain of the ECM using a mechanical strain device — to rapidly simulate longterm ECM straining by myofibroblasts — correlated with increased levels of TGFβ1 activation by human DMF contraction. Furthermore, at high levels of ECM pre-strain, TGFβ could be activated in the absence of human DMFs, and the strain threshold for this was lower for DMF ECM than for DF ECM, which is in keeping with the greater level of organization of the DMF ECM. The results suggest that mechanical pre-straining of the ECM determines the efficacy of TGFβ activation, which sets a mechanical threshold for the pro-fibrotic activity of myofibroblasts. Manipulating this threshold could have important implications for normal versus fibrotic tissue repair. Kirsty Minton ORIGINAL RESEARCH PAPER Klingberg, F. et al. Prestress in the extracellular matrix sensitizes latent TGF‑β1 for activation. J. Cell Biol. http:// dx.doi.org/10.1083/jcb.201402006 (2014)
VOLUME 15 | DECEMBER 2014 © 2014 Macmillan Publishers Limited. All rights reserved
E X T R A C E L L U L A R M AT R I X
Preconditioning the ECM for fibrosis differences in ECM structure might affect contractioninduced TGFβ1 activation Sagittal section of a mechanically restrained rat skin wound showing that activation of myofibroblasts (α-smooth muscle actin, blue) associates with high fibrillar organization of fibronectin (red) and LTBP1 (green). Image courtesy of Boris Hinz, University of Toronto, Canada.
Remodelling of the extracellular matrix (ECM) by myofibroblasts is crucial for wound repair, but if dysregulated can result in pathological fibrosis. Hinz and colleagues describe how pre-organization of the ECM by myofibroblasts can prime for increased fibrosis by regulating the activation of the pro-fibrotic cytokine transforming growth factor-β (TGFβ). Latent TGFβ is secreted bound to latency-associated peptide (LAP), which binds to the ECM protein latent TGFβ-binding protein 1 (LTBP1). Integrin-dependent binding of contracting myofibroblasts to LAP induces a conformational change in LAP that releases active
TGFβ from the ECM. Therefore, the short-term contractile state of the wound determines the activity of TGFβ. New work now shows that this process is augmented by longerterm changes to the organization of the ECM. In a rat model of wound healing, restraining the wound edges mechanically resulted in accelerated expression of ECM proteins such as fibronectin and LTBP1, and increased fibril organization of the ECM, which correlated with increased TGFβ1 signalling. This increased ECM organization was the result of increased strain exerted by myofibroblasts. Highcontractile human dermal myo fibroblasts (DMFs) had increased expression of ECM proteins compared with low-contractile human dermal fibroblasts (DFs), and there was greater organization of LTBP1 and fibronectin in the DMF ECM than in the DF ECM. Moreover, cell contraction resulted in threefold higher levels of active TGFβ1 in human DMF cultures compared with human DF cultures. This indicates that differences in ECM structure might affect contractioninduced TGFβ1 activation. In support of this, when decellularized ECM from human DMFs and from human DFs was reseeded with human DMFs, DMF contraction-induced activation of TGFβ1 was twofold greater from DMF-remodelled ECM than from
NATURE REVIEWS | MOLECULAR CELL BIOLOGY
DF-remodelled ECM, despite similar total levels of TGFβ1. This correlated with the extent of ECM organization, which was significantly higher in DMF cultures than in DF cultures. The authors confirmed that preorganization of the ECM affects TGFβ1 activation using Fak–/– mouse embryonic fibroblasts, which have a disorganized ECM with a low fibril density and are defective for TGFβ activation. Increasing the pre-strain of the ECM using a mechanical strain device — to rapidly simulate longterm ECM straining by myofibroblasts — correlated with increased levels of TGFβ1 activation by human DMF contraction. Furthermore, at high levels of ECM pre-strain, TGFβ could be activated in the absence of human DMFs, and the strain threshold for this was lower for DMF ECM than for DF ECM, which is in keeping with the greater level of organization of the DMF ECM. The results suggest that mechanical pre-straining of the ECM determines the efficacy of TGFβ activation, which sets a mechanical threshold for the pro-fibrotic activity of myofibroblasts. Manipulating this threshold could have important implications for normal versus fibrotic tissue repair. Kirsty Minton ORIGINAL RESEARCH PAPER Klingberg, F. et al. Prestress in the extracellular matrix sensitizes latent TGF‑β1 for activation. J. Cell Biol. http:// dx.doi.org/10.1083/jcb.201402006 (2014)
VOLUME 15 | DECEMBER 2014 © 2014 Macmillan Publishers Limited. All rights reserved
