Cell Biology Contraction-Mediated Release of TGF-β1

Nancy R. Gough

Science Signaling, AAAS, Washington, DC 20005, USA

Wound healing requires the contraction of the tissue, which in turn involves the conversion of fibroblasts into myofibroblasts, which exhibit high contractility generated by smooth muscle actin stress fibers. In fibrotic diseases, myofibroblasts contribute to tissue fibrosis. Transforming growth factor-β1 (TGF-β1) and mechanical stress are both required for myofibroblast formation. Wipff et al. show that myofibroblasts also contribute to the activation of latent TGF-β1, which is secreted and sequestered in the extracellular matrix (ECM) bound to latency associated protein (LAP) and latent TGF-β binding protein 1 (LTBP-1), through a contraction-mediated mechanism. The authors developed a culture system consisting of fibroblasts or myofibroblasts, transformed mink lung reporter cells (TMLCs) that produce luciferase in the presence of active TGF-β1, and extracted ECM containing latent TGF-β1. They used this system to show that myofibroblasts stimulated the release of active TGF-β1 to a greater extent than did other types of fibroblasts. Furthermore, agonists that triggered myofibroblast contraction promoted TGF-β1 release, whereas drugs that inhibited contraction prevented contraction-stimulating agonists from stimulating TGF-β1 release without affecting basal TGF-β1 release. Proteolysis is one known mechanism for releasing active TGF-β1 from the latent complex bound to the ECM; however, protease inhibitors failed to block TGF-β1 release triggered by myofibroblast contraction. TGF-β1 release triggered by myofibroblast contraction was blocked by interfering with the interaction between integrins and LAP or by function-blocking antibodies to vβ5 integrin. By culturing the myofibroblasts on silicone membranes and then subjecting the cells to stretch, the authors showed that stretch stimulated TGF-β1 release and that this required an intact cytoskeleton. Substrate stiffness was also important for contraction-mediated release of TGF-β1. Monitoring the movement of LTBP-1 in response to myofibroblast contraction showed that LTBP-1 was displaced toward the center of the myofibroblast when present in soft substrates. In stiffer substrates, LTBP-1 was not displaced toward the center and, instead, sometimes the LTBP-1-labeled fibers were straighter after myofibroblast contraction. The authors propose a model whereby integrins on the myofibroblast grab LAP and then when the myofibroblast contracts, this pulls against the ECM and releases TGF-β1. Thus, the stiffness of the ECM and ECM remodeling at the wound site may contribute to TGF-β1 release.

P.-J. Wipff, D. B. Rifkin, J.-J. Meister, B. Hinz, Myofibroblast contraction activates latent TGF-β1 from the extracellular matrix. J. Cell Biol. 179, 1311-1323 (2007). [Abstract] [Full Text]

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