Mechanical and Physical Regulation of Fibroblast–Myofibroblast Transition: From Cellular Mechanoresponse to Tissue Pathology

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.

Airway-On-A-Chip: Designs and Applications for Lung Repair and Disease

“…Fibroblasts are the most abundant cell type found in the lung interstitium, playing a crucial role in airway repair, remodeling, and inflammation. The primary function of lung fibroblasts is the production of ECM proteins (i.e., type I and III collagen, elastin, fibronectin, and proteoglycans) [ 41 , 42 ]. However, they also secrete metalloproteinases to trigger ECM degradation and inflammatory signals such as tumor necrosis factor- post injury [ 42 ].…”

“…The primary function of lung fibroblasts is the production of ECM proteins (i.e., type I and III collagen, elastin, fibronectin, and proteoglycans) [ 41 , 42 ]. However, they also secrete metalloproteinases to trigger ECM degradation and inflammatory signals such as tumor necrosis factor- post injury [ 42 ]. Under various stimuli (i.e., mechanical cues, changes in microenvironment, cellular communication), lung fibroblasts undergo migration, proliferation, activation, and differentiate into contractive myofibroblasts [ 43 ].…”

“…Under various stimuli (i.e., mechanical cues, changes in microenvironment, cellular communication), lung fibroblasts undergo migration, proliferation, activation, and differentiate into contractive myofibroblasts [ 43 ]. The presence of myofibroblasts is a key hallmark of many respiratory diseases as they are associated with increased ECM deposition and the development of fibrotic tissue [ 42 ].…”

Fibrosis: Sirtuins at the checkpoints of myofibroblast differentiation and profibrotic activity

“…2,[14][15][16][17][18] Following injury, fibroblasts at the site of injury activate and undergo a phenotype switch to become myofibroblasts, the so-called fibroblast-to-myofibroblast transition (FMT). 19 EndMT, EMT and FMT can be triggered by TGF-β and induce the generation of active profibrotic myofibroblasts. 2,13,19…”

“…19 EndMT, EMT and FMT can be triggered by TGF-β and induce the generation of active profibrotic myofibroblasts. 2,13,19…”