title: Interstitial fluid flow induces myofibroblast differentiation and collagen alignment in vitro.
abstract: The differentiation of fibroblasts to contractile myofibroblasts, which is characterized by de novo expression of alpha-smooth muscle actin (alpha-SMA), is crucial for wound healing and a hallmark of tissue scarring and fibrosis. These processes often follow inflammatory events, particularly in soft tissues such as skin, lung and liver. Although inflammatory cells and damaged epithelium can release transforming growth factor beta1 (TGF-beta1), which largely mediates myofibroblast differentiation, the biophysical environment of inflammation and tissue regeneration, namely increased interstitial flow owing to vessel hyperpermeability and/or angiogenesis, may also play a role. We demonstrate that low levels of interstitial (3D) flow induce fibroblast-to-myofibroblast differentiation as well as collagen alignment and fibroblast proliferation, all in the absence of exogenous mediators. These effects were associated with TGF-beta1 induction, and could be eliminated with TGF-beta1 blocking antibodies. Furthermore, alpha1beta1 integrin was seen to play an important role in the specific response to flow, as its inhibition prevented fibroblast differentiation and subsequent collagen alignment but did not block their ability to contract the gel in a separate floating gel assay. This study suggests that the biophysical environment that often precedes fibrosis, such as swelling, increased microvascular permeability and increased lymphatic drainage--all which involve interstitial fluid flow--may itself play an important role in fibrogenesis.
authors.affiliation: Department of Chemical and Biological Engineering, Northwestern University, Evanston, 633 Clark Street, Chicago, IL 60208, USA.
authors.forename: Chee Ping
authors.initials: CP
authors.lastname: Ng
authors.forename: Boris
authors.initials: B
authors.lastname: Hinz
authors.forename: Melody A
authors.initials: MA
authors.lastname: Swartz
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism*; D045604:Extracellular Fluid / Q000502:physiology*; D005109:Extracellular Matrix / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D039222:Integrin alpha1beta1 / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
chemical_list: D039222:Integrin alpha1beta1; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003094:Collagen