Synthetic fibrous hydrogels as a platform to decipher cell-matrix mechanical interactions

Abstract

The interactions between cells and their direct environment are crucial for cell fate but biochemically and mechanically highly complex, and therefore, poorly understood. Despite recent advances that exposed the impact of a range of different factors, real progress remains challenging, since appropriate controllable matrices and quantitative analysis techniques that cover a range of time and length scales are unavailable. Here, we use a synthetic fibrous hydrogel with nonlinear mechanics to mimic and tailor the bi-directional cell-matrix interactions. Using advanced microscopy-based approaches, we acquire a comprehensive picture of how cellular traction forces, fiber remodeling, matrix stiffening, matrix properties and cellular behavior interact, highlighting for instance, the importance of a fibrous architecture and nonlinear mechanics of the matrix. Complete mapping of cell-matrix interactions at the cellular length scale provides indispensable information for the rational design of biomimetic materials to recreate realistic in vitro cell environments.

Nonlinear Elastic Bottlebrush Polymer Hydrogels Modulate Actomyosin Mediated Protrusion Formation in Mesenchymal Stromal Cells

“…However, at 𝜎 𝑐,𝑒𝑞𝑢𝑖𝑙 < 30 Pa (Figure 3aiv-vi), we observe a transition from primarily spherical cellular morphologies just outside the BRSR -PEG-2k, 2.5wt% formulation (𝜎 𝑐,𝑒𝑞𝑢𝑖𝑙 = 27 Pa)to the initial appearance of spindle-like protrusions in PPEGA9-80 formulation just within the BRSR (𝜎 𝑐,𝑒𝑞𝑢𝑖𝑙 = 22 Pa). A similar protrusive phenotype for human adipose-derived stem cells and fibroblasts has been observed within synthetic and natural fibrous hydrogels, which exhibit strain-stiffening within the BRSR [26,33,34] . However, these previous findings are confounded by the propensity of fibrous materials to also stress-relax, making it difficult to definitively determine the impact of strain-stiffening mechanics on cell behavior.…”

Hybrid cellular Potts and bead-spring modeling of cells in fibrous extracellular matrix

“…Long-ranged propagation of cell-mediated strains is a distinguishing feature of ECM gels with fibers on the same scale as cells (13,25), and it has been implicated in cell alignment and tissue morphogenesis (3,13,(101)(102)(103)(104). We tracked the displacement of fibers initially located within a defined radius from the cell center, a common metric to quantify cell force propagation (3,5,25,43). Like for fiber densification, fiber displacement at the final simulation state varied nonlinearly with cross-linker density (Fig.…”

“…These models assume infinitesimal strains, such that the ECM concentration is always isotropic. Therefore, such models struggle to explain phenomena such as ECM accumulation near contractile cells and long-ranged force transmission (5,(23)(24)(25). Since the characteristic length scale of ECM fibers is large compared with the cell size, the interface between cells and fibrous ECM is best represented by a discrete model (12,13,26).…”