Multiscale mechanobiology: computational models for integrating molecules to multicellular systems

Abstract

Mechanical signals exist throughout the biological landscape. Across all scales, these signals, in the form of force, stiffness, and deformations, are generated and processed, resulting in an active mechanobiological circuit that controls many fundamental aspects of life, from protein unfolding and cytoskeletal remodeling to collective cell motions. The multiple scales and complex feedback involved present a challenge for fully understanding the nature of this circuit, particularly in development and disease in which it has been implicated. Computational models that accurately predict and are based on experimental data enable a means to integrate basic principles and explore fine details of mechanosensing and mechanotransduction in and across all levels of biological systems. Here we review recent advances in these models along with supporting and emerging experimental findings.

Cellular adaptation to biomechanical stress across length scales in tissue homeostasis and disease

“…Furthermore, to treat diseases that include an element of defective mechanotransduction, putative compounds must be tested in the appropriate 3D matrix mechanics to accurately predict responses [116], and active efforts to develop compounds that selectively target key elements of the mechanotransduction pathway will be critical [117]. New mechanistic insights into how cells sense and respond to tissue mechanics will follow from the widespread implementation of in silico modeling [118] to develop complex cell-cell and cell-matrix models [92,97,106,119], and the development of 3D models to systematically tease apart the influence of diverse matrix mechanical properties, biomolecules, and genetic alterations on cell behaviors and fate in a controlled manner [120-123]. …”

Single-Cell Migration in Complex Microenvironments: Mechanics and Signaling Dynamics

“…Recent modeling approaches of cell signaling and mechanics at multiple scales are reviewed in Refs. [84,125]. In particular, in vivo conditions often have a combination of biochemical and mechanical cues, but competing or synergistic effects from simultaneous cues are not well characterized.…”

“…Tumors can align collagen through Rho kinase-mediated contractility, while this pathway becomes less prominent in driving tumor invasion in pre-aligned matrices [52]. Additionally, the fibrillar architecture of the ECM is conducive to long range force transmission by contractile cells [79,80], potentially leading to mechanotransduction in distal cells [81,82] and modulating binding kinetics of matrix proteins such as fibronectin [83,84].…”

Molecular simulations of cellular processes

“…Simulating macromolecule stability and interactions in a eukaryotic-like cell requires a large effort for the presence of localized and pervasive structures (Neri et al 2013;Smith et al 2014;Unterberger and Holzapfel 2014;Mak et al 2015Mak et al , 2016Gao et al 2015;Nguyen et al 2016;Popov et al 2016;Reddy and Sansom 2016;Chavent et al 2016;Foffano et al 2016;Niesen et al 2017;Tachikawa and Mochizuki 2017). Future investigations will be devoted to simulating dynamical processes involving the cytoskeleton and the membranes, such as the trafficking of macromolecules and vesicles to their sub-cellular localization (Miller et al 2016).…”