Guiding 3D cell migration in deformed synthetic hydrogel microstructures

Abstract

The ability of cells to navigate through the extracellular matrix, a network of biopolymers, is controlled by an interplay of cellular activity and mechanical network properties. Synthetic hydrogels with highly tuneable compositions and elastic properties are convenient model systems for the investigation of cell migration in 3D polymer networks. To study the impact of macroscopic deformations on single cell migration, we present a novel method to introduce uniaxial strain in matrices by microstructuring photo-polymerizable hydrogel strips with embedded cells in a channel slide. We find that such confined swelling results in a strained matrix in which cells exhibit an anisotropic migration response parallel to the strain direction. Surprisingly, however, the anisotropy of migration reaches a maximum at intermediate strain levels and decreases strongly at higher strains. We account for this non-monotonic response in the migration anisotropy with a computational model, in which we describe a cell performing durotactic and proteolytic migration in a deformable elastic meshwork. Our simulations reveal that the macroscopically applied strain induces a local geometric anisotropic stiffening of the matrix. This local anisotropic stiffening acts as a guidance cue for directed cell migration, resulting in a non-monotonic dependence on strain, as observed in our experiments. Our findings provide a mechanism for mechanical guidance that connects network properties on the cellular scale to cell migration behaviour.

Anomalously diffusing and persistently migrating cells in 2D and 3D culture environments

“…This reduces the speed and MSD as a function of time, and, at our imaging resolution, results in alpha values below that of free diffusion, or diffusion in a solvent. The AD model has been used in similar MMP-degradable PEG-based hydrogels in recent work, where cells exhibited anomalous diffusion with an exponent between 1.4 and 1.8 19 . We observed cells doubling back along degraded tracks, leading to more subdiffusive behaviors than this recent report, but that α increased significantly for cells in patient 1 and patient 2 MSC-conditioned medium compared to control medium.…”

Effect of Nuclear Stiffness on Cell Mechanics and Migration of Human Breast Cancer Cells

“…Cell migration and invasion are inherently coupled to cell mechanics and matrix environmental mechanics (Mierke et al, 2008(Mierke et al, , 2011a(Mierke et al, ,b, 2018Baker and Chen, 2012;Fruleux and Hawkins, 2016;Dietrich et al, 2018;Mierke, 2019a), or in other words their elastic properties, such as stiffness. Cell mechanics are intertwined with matrix mechanics, since the environmental mechanics can alter cell mechanics and in turn cells can remodel the surrounding matrix environment by exerting forces on it (Wolf et al, 2009(Wolf et al, , 2013Mierke, 2011;Mierke et al, 2011bMierke et al, , 2017Fischer et al, 2017;Kunschmann et al, 2019).…”

Bridging the gap between single-cell migration and collective dynamics

“…However, a fully mechanistic understanding of how these basic functionalities are integrated into single-cell migration and coordinated multicellular movement is still lacking.Here, we present a computational model which en- * These two authors contributed equally.ables us to study cell migration at various scales, and thus provides an integrative perspective on the basic cell functions that enable the emergence of collective cell migration. While a variety of very successful modeling approaches has been used to describe single-cell dynamics [14][15][16][17][18][19][20][21][22][23] or the movements of extended tissues [24][25][26][27][28][29][30][31], these models are hard to reconcile with each other. Models that focus on single cells are typically difficult to extend to larger cell numbers, largely due to their computational complexity.…”