22 Chapter 2 Stiffness and Viscoelasticity Changes in the biomechanics of fibrotic lung tissue result directly from the altered and abnormal distribution and modification of the ECM proteins in lung fibrosis. Lung ECM has a viscoelastic nature that can dissipate the stress applied to it via various sources, such as mechanical forces changing with breathing in and out [10]. Among many biomechanical parameters, stiffness of the tissue is strongly associated with lung fibrosis and has been well-documented: native IPF lung samples were shown to have higher stiffness than control lung samples (1.96 ± 0.13 kPA vs 16.52 ± 2.25 kPA) and this difference remained similar also in decellularized lung samples (IPF lung sample: 7.34 ± 0.6 kPa, control lung sample: 1.6 ± 0.08 kPA) [9, 10]. Stiffness, like many other mechanotransducers, induces the Hippo pathway through yes-associated protein (YAP) – PDZ-binding motif (TAZ) signaling, resulting in the perpetuation of fibrosis [30]. Several in vitro models have been developed to assess the effect of stiffness on lung cells: fibroblasts cultured on 2D hydrogels with higher stiffness were shown to migrate faster, along with a greater cell spread area, compared to the fibroblasts cultured on hydrogels with lower (more physiological-like) stiffness [31]. Similarly, a stiffer 2D culture environment was shown to increase fibroblast activation via chromatin remodeling compared to softer surfaces, accompanied by increased nuclear volume in these fibroblasts [32]. Higher stiffness of fibronectin coated polyacrylamide hydrogels was shown to decrease fibroblast activating protein expression while increasing the cell spreading area and αSMA expression in murine lung fibroblasts compared with softer hydrogels; on the other hand, changes in the stiffness of collagen type I coated polyacrylamide hydrogels did not change the cellular response [33]. Likewise, comparing the effect of different stiffness values of polyacrylamide hydrogels and incorporation of solubilized matrix from healthy or IPF lungs on pericytes seeded on these hydrogels showed that increased cell area and higher expression of αSMA resulted from the increase in the stiffness of the hydrogel rather than the ECM composition [26]. Interestingly, a study by Matera et al. suggested opposing effects of stiffness on lung fibroblasts in 2D and 3D cultures: higher stiffness of 2D cultures promoted myofibroblast differentiation while stiffer 3D cultures limited the differentiation of the lung fibroblasts [12]. Lastly, blocking the YAP – TAZ pathway of mechanotransduction in IPF lung-derived fibroblasts resulted in decreased expression of ECM proteins while ECM-degradation enzyme gene expression levels increased compared to the untreated IPF fibroblasts [34]. All of these studies together indicate different effects of stiffness on cells. It is highly possible that the combination of altered composition and increased stiffness induces different cellular responses in different cells. More investigation on separating the contribution of altered composition and stiffness of the fibrotic microenvironment
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