Abstract
Fibroblasts are cells present throughout the human body that are primarily responsible for the production and maintenance of the extracellular matrix (ECM) within the tissues. They have the capability to modify the mechanical properties of the ECM within the tissue and transition into myofibroblasts, a cell type that is associated with the development of fibrotic tissue through an acute increase of cell density and protein deposition. This transition from fibroblast to myofibroblast—a well-known cellular hallmark of the pathological state of tissues—and the environmental stimuli that can induce this transition have received a lot of attention, for example in the contexts of asthma and cardiac fibrosis. Recent efforts in understanding how cells sense their physical environment at the micro- and nano-scales have ushered in a new appreciation that the substrates on which the cells adhere provide not only passive influence, but also active stimulus that can affect fibroblast activation. These studies suggest that mechanical interactions at the cell–substrate interface play a key role in regulating this phenotype transition by changing the mechanical and morphological properties of the cells. Here, we briefly summarize the reported chemical and physical cues regulating fibroblast phenotype. We then argue that a better understanding of how cells mechanically interact with the substrate (mechanosensing) and how this influences cell behaviors (mechanotransduction) using well-defined platforms that decouple the physical stimuli from the chemical ones can provide a powerful tool to control the balance between physiological tissue regeneration and pathological fibrotic response.
Highlights
Fibroblasts are cells belonging to the mesenchyme that are capable of producing and modifying extracellular matrix (ECM) components such as fibronectin and collagen (Kanekar et al, 1998)
This phenotype transition is defined as Fibroblast-to-Myofibroblast Transition (FMT)
It was shown that other growth factors have a well-coordinated activity with TGF-β to promote Fibroblast-to-myofibroblast transition (FMT), such as CTGF (Kular et al, 2011), PDGF, which increases the number of migrating cells and encourages phenotypical shifts of lung fibroblast toward myofibroblasts (Malmström et al, 2003), as well as NGF (Bonini et al, 1996) and IGF-1 (Yamashita et al, 2005; Boero et al, 2007) in different tissues
Summary
Fibroblasts are cells belonging to the mesenchyme that are capable of producing and modifying extracellular matrix (ECM) components such as fibronectin and collagen (Kanekar et al, 1998). One critical pathway is the TGF-β pathway (Wynn and Ramalingam, 2012; Rockey et al, 2015) This pathway can strongly impact the transition of fibroblasts to a myofibroblast phenotype, which involves alpha smooth muscle actin (α-SMA) production with stress-fiber-like appearance, further leading to migration, proliferation, and production of ECM components such as collagen type 1 that changes the mechanical and physical properties of the environment. A key step in wound healing, and in fibrotic pathological diseases, is the activation of the fibroblast to become myofibroblast, where they escape the entrance to a quiescent state or the apoptosis pathway (Gabbiani et al, 1971) This phenotype transition is defined as Fibroblast-to-Myofibroblast Transition (FMT). The formation of stress fibers that promote cell motility can be induced by the presence of growth factors (Malmström et al, 2003), suggesting the role of environmental humoral stimuli in FMT
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