TY - JOUR
T1 - Suppression of the fibrotic encapsulation of silicone implants by inhibiting the mechanical activation of pro-fibrotic TGF-β
AU - Noskovicova, Nina
AU - Schuster, Ronen
AU - van Putten, Sander
AU - Ezzo, Maya
AU - Koehler, Anne
AU - Boo, Stellar
AU - Coelho, Nuno M.
AU - Griggs, David
AU - Ruminski, Peter
AU - McCulloch, Christopher A.
AU - Hinz, Boris
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021
Y1 - 2021
N2 - The fibrotic encapsulation of implants involves the mechanical activation of myofibroblasts and of pro-fibrotic transforming growth factor beta 1 (TGF-β1). Here, we show that both softening of the implant surfaces and inhibition of the activation of TGF-β1 reduce the fibrotic encapsulation of subcutaneous silicone implants in mice. Conventionally stiff silicones (elastic modulus, ~2 MPa) coated with a soft silicone layer (elastic modulus, ~2 kPa) reduced collagen deposition as well as myofibroblast activation without affecting the numbers of macrophages and their polarization states. Instead, fibroblasts around stiff implants exhibited enhanced intracellular stress, increased the recruitment of αv and β1 integrins, and activated TGF-β1 signalling. In vitro, the recruitment of αv integrin to focal adhesions and the activation of β1 integrin and of TGF-β were higher in myofibroblasts grown on latency-associated peptide (LAP)-coated stiff silicones than on soft silicones. Antagonizing αv integrin binding to LAP through the small-molecule inhibitor CWHM-12 suppressed active TGF-β signalling, myofibroblast activation and the fibrotic encapsulation of stiff subcutaneous implants in mice.
AB - The fibrotic encapsulation of implants involves the mechanical activation of myofibroblasts and of pro-fibrotic transforming growth factor beta 1 (TGF-β1). Here, we show that both softening of the implant surfaces and inhibition of the activation of TGF-β1 reduce the fibrotic encapsulation of subcutaneous silicone implants in mice. Conventionally stiff silicones (elastic modulus, ~2 MPa) coated with a soft silicone layer (elastic modulus, ~2 kPa) reduced collagen deposition as well as myofibroblast activation without affecting the numbers of macrophages and their polarization states. Instead, fibroblasts around stiff implants exhibited enhanced intracellular stress, increased the recruitment of αv and β1 integrins, and activated TGF-β1 signalling. In vitro, the recruitment of αv integrin to focal adhesions and the activation of β1 integrin and of TGF-β were higher in myofibroblasts grown on latency-associated peptide (LAP)-coated stiff silicones than on soft silicones. Antagonizing αv integrin binding to LAP through the small-molecule inhibitor CWHM-12 suppressed active TGF-β signalling, myofibroblast activation and the fibrotic encapsulation of stiff subcutaneous implants in mice.
U2 - 10.1038/s41551-021-00722-z
DO - 10.1038/s41551-021-00722-z
M3 - Journal article
C2 - 34031559
AN - SCOPUS:85106250532
VL - 5
SP - 1437
EP - 1456
JO - Nature Biomedical Engineering
JF - Nature Biomedical Engineering
SN - 2157-846X
ER -