Abstract
Cells can sense forces applied to them, but also the stiffness of their environment. These are two different phenomena, and here we investigate the mechanosensitivity of the 2nd kind: how the cell can measure an elastic modulus at a single point of adhesion—and how the cell can receive and interpret the chemical signal released from the sensor. Our model uses the example of large latent complex of TGF-β as a sensor. Stochastic theory gives the rate of breaking of latent complex, which initiates the signaling feedback loop after the active TGF-β release and leads to a change of cell phenotype driven by the α-smooth muscle actin. We investigate the dynamic and steady-state behaviors of the model, comparing them with experiments. In particular, we analyse the timescale of approach to the steady state, the stability of the non-linear dynamical system, and how the steady-state concentrations of the key markers vary depending on the elasticity of the substrate. We discover a crossover region for values of substrate elasticity closely corresponding to that of the fibroblast to myofibroblast transition. We suggest that the cell could actively vary the parameters of its dynamic feedback loop to ‘choose’ the position of the transition region and the range of substrate elasticity that it can detect. In this way, the theory offers the unifying mechanism for a variety of phenomena, such as the myofibroblast conversion in fibrosis of wounds and lungs and smooth muscle cell dysfunction in cardiac disease.
Highlights
How cells sense is important to life: homeostasis necessitates sensors
Stochastic theory gives the rate of breaking of latent complex, which initiates the signaling feedback loop after the active TGF-β release and leads to a change of cell phenotype driven by the α-smooth muscle actin
The corresponding Young’s modulus where the fibroblast transition occurs lies in between these two extremes, as required by our fitting parameter. Over this transition β increases from 6cell−1 to a final value of 108cell−1. These values correspond to real concentrations of about 0.48ng/ml and 8.6ng/ml, respectively—taking TGF-β molecular mass as 25kDa [44] and assuming the fibroblast is a spherical cell with a radius of 5μm
Summary
How cells sense is important to life: homeostasis necessitates sensors. The relationship between cell morphology and chemical properties of its environment have long been understood and documented. This is consistent with descriptions of force induced TGF-β activation by binding of αvβ to the latent complex [12] In this case the range of the scaled (non-dimensional) k~ is between 4 Á 104 at the upper bound of rigid glass, 0.02 for a typical gel or muscle tissue, down to 8 Á 10−5 at the lowest bound of E = 100 Pa. The effective diffusion constant D~ , the rate of mechanical breaking km, is twhheircahtieonkteBrTs=aps affigffiffi1cffigffioffi2ffiffimremfleocntifnagcttohreignetohme eetxrpicremsseiaonn for of the damping coefficients (loss factors) of the substrate and the latent complex (see [16] for detail). Clealry the jigsaw pieces of this model fit together well
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