Effect of Loading History on Airway Smooth Muscle Cell-Matrix Adhesions

Abstract

Integrin-mediated adhesions between airway smooth muscle (ASM) cells and the extracellular matrix (ECM) regulate how contractile forces generated within the cell are transmitted to its external environment. Environmental cues are known to influence the formation, size, and survival of cell-matrix adhesions, but it is not yet known how they are affected by dynamic fluctuations associated with tidal breathing in the intact airway. Here, we develop two closely related theoretical models to study adhesion dynamics in response to oscillatory loading of the ECM, representing the dynamic environment of ASM cells in vivo. Using a discrete stochastic-elastic model, we simulate individual integrin binding and rupture events and observe two stable regimes in which either bond formation or bond rupture dominate, depending on the amplitude of the oscillatory loading. These regimes have either a high or low fraction of persistent adhesions, which could affect the level of strain transmission between contracted ASM cells and the airway tissue. For intermediate loading, we observe a region of bistability and hysteresis due to shared loading between existing bonds; the level of adhesion depends on the loading history. These findings are replicated in a related continuum model, which we use to investigate the effect of perturbations mimicking deep inspirations (DIs). Because of the bistability, a DI applied to the high adhesion state could either induce a permanent switch to a lower adhesion state or allow a return of the system to the high adhesion state. Transitions between states are further influenced by the frequency of oscillations, cytoskeletal or ECM stiffnesses, and binding affinities, which modify the magnitudes of the stable adhesion states as well as the region of bistability. These findings could explain (in part) the transient bronchodilatory effect of a DI observed in asthmatics compared to a more sustained effect in normal subjects.

Shortening of airway smooth muscle is modulated by prolonging the time without simulated deep inspirations in ovine tracheal strips

“…It will be very important in future studies to determine the sensitivity of these different extracellular connections to mechanical strain and their rate of reformation after rupture. This is further supported by recent theoretical models showing the importance of cell-matrix connections in determining both the level of strain transmission on ASM during breathing maneuvers and the level the bronchodilation afforded by a DI (27).…”

Extracellular matrix stiffness regulates human airway smooth muscle contraction by altering the cell-cell coupling

“…These cells are constantly subjected to periodic stretch associated with tidal breathing and deep breaths. Modeling studies show that the connected nature of a smooth muscle ensemble can influence how the airway responds to deep breaths 41 . The extent to which fluctuating levels of stretch might impact our primary findings is therefore of great interest but is beyond the scope of the current work.…”

Switching behaviour in vascular smooth muscle cell–matrix adhesion during oscillatory loading

“…In particular, Walcott et al (2011) show that the different stiffness-dependent behaviours emerge naturally when load-dependent reaction rates are considered. In addition to the effect of static loads, previous studies incorporating oscillatory loading (Kong et al, 2008;Irons et al, 2018) predict that oscillation amplitude, frequency and material stiffnesses all affect cluster stability. In our previous modelling study (Irons et al, 2018), we further predicted the existence of a bistable adhesion regime, where mechanical cooperativity and cell deformation could promote increased integrin adhesion instead of a lower adhesion state.…”

“…In addition to the effect of static loads, previous studies incorporating oscillatory loading (Kong et al, 2008;Irons et al, 2018) predict that oscillation amplitude, frequency and material stiffnesses all affect cluster stability. In our previous modelling study (Irons et al, 2018), we further predicted the existence of a bistable adhesion regime, where mechanical cooperativity and cell deformation could promote increased integrin adhesion instead of a lower adhesion state. A consequence of this bistability is that loading history affects future adhesion dynamics.…”

“…In the present study, we use both in vitro AFM experiments and a deterministic mathematical model related to our previous work (Irons et al, 2018), to measure and predict the integrin response to fixed amplitude vertical oscillations of the AFM probe. In both the experimental and theoretical results, as the amplitude of oscillatory loading increases we observe a transition between states of firm adhesion and of complete integrin detachment from the ECM.…”