Enhanced fibroblast contraction of 3D collagen lattices and integrin expression by TGF-beta1 and -beta3: mechanoregulatory growth factors?
Generation of contractile forces as fibroblasts attach and migrate through collagenous substrates is a fundamental behavior, yet its regulation and consequences are obscure. Although the transforming growth factor-betas (TGF-beta) are similarly important in fibrosis and tissue repair, their role in contraction is controversial. Using a quantitative, 3D collagen culture model we have measured the effects of TGF-beta1 and -beta3 on contractile forces generated by human dermal fibroblasts. Maximal stimulation was between 7.5 and 15 ng/ml of TGF-beta1. Higher doses were inhibitory (30 ng/ml), giving a bell-shaped dose response. The initial rate of force generation was increased sevenfold (15 ng/ml). A similar response pattern was seen with TGF-beta3 alone. However, the addition of both isoforms together stimulated a biphasic increase in force generation, suggesting that there was a distinct temporal cooperativity between the two isforms. This very early onset (10-20 min) of stimulation suggested that TGF-beta might act through cell attachment and integrin function and the effect of TFG-beta on expression of fibronectin (FnR) and vitronectin (VnR) integrin receptors was monitored over the same time scale. TGF-beta1 dramatically up-regulated VnR expression, relative to FnR, over time but the optimal time for this was 2-4 h later than that of force stimulation. It is concluded that TGF-beta1 and -beta3 behave here primarily as mechanoregulatory growth factors and that stimulation of integrin expression may be a consequence of the altered cell stress.
Brown
Robert A
RA
Tissue Repair Unit, Centre for Plastic and Reconstructive Surgery, University College London, RFUCMS, 67 Riding House Street, London, W1W 7EJ, United Kingdom.
Sethi
Kamaljit K
KK
Gwanmesia
Ivo
I
Raemdonck
David
D
Eastwood
Mark
M
Mudera
Vivek
V
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D001696:Biomechanical Phenomena; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism / Q000494:pharmacology*; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D016023:Integrins / Q000187:drug effects / Q000378:metabolism*; D017469:Receptors, Fibronectin / Q000187:drug effects / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000187:drug effects / Q000378:metabolism; D013314:Stress, Mechanical; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3
D016023:Integrins; D017469:Receptors, Fibronectin; D019030:Receptors, Vitronectin; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3; D003094:Collagen