Ng Chee Ping, Hinz Boris, Swartz Melody A
Department of Chemical and Biological Engineering, Northwestern University, Evanston, 633 Clark Street, Chicago, IL 60208, USA.
J Cell Sci. 2005 Oct 15;118(Pt 20):4731-9. doi: 10.1242/jcs.02605. Epub 2005 Sep 27.
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.
成纤维细胞向收缩性肌成纤维细胞的分化，其特征为α平滑肌肌动蛋白（α-SMA）的从头表达，对伤口愈合至关重要，是组织瘢痕形成和纤维化的一个标志。这些过程通常继发于炎症事件之后，尤其是在皮肤、肺和肝脏等软组织中。尽管炎症细胞和受损上皮细胞可释放转化生长因子β1（TGF-β1），其在很大程度上介导肌成纤维细胞的分化，但炎症和组织再生的生物物理环境，即由于血管通透性增加和/或血管生成导致的间质液流动增加，也可能起作用。我们证明，低水平的间质（三维）流动可诱导成纤维细胞向肌成纤维细胞的分化以及胶原蛋白排列和成纤维细胞增殖，所有这些均在无外源性介质的情况下发生。这些效应与TGF-β1的诱导有关，并且可以用TGF-β1阻断抗体消除。此外，α1β1整合素在对流动的特异性反应中起重要作用，因为其抑制作用可阻止成纤维细胞分化和随后的胶原蛋白排列，但不会在单独的漂浮凝胶试验中阻断它们收缩凝胶的能力。这项研究表明，通常先于纤维化的生物物理环境，如肿胀、微血管通透性增加和淋巴引流增加——所有这些都涉及间质液流动——其本身可能在纤维化形成中起重要作用。
