Local 3D matrix microenvironment regulates cell migration through spatiotemporal dynamics of contractility-dependent adhesions

Abstract

The physical properties of two-dimensional (2D) extracellular matrices (ECMs) modulate cell adhesion dynamics and motility, but little is known about the roles of local microenvironmental differences in three-dimensional (3D) ECMs. Here we generate 3D collagen gels of varying matrix microarchitectures to characterize their regulation of 3D adhesion dynamics and cell migration. ECMs containing bundled fibrils demonstrate enhanced local adhesion-scale stiffness and increased adhesion stability through balanced ECM/adhesion coupling, whereas highly pliable reticular matrices promote adhesion retraction. 3D adhesion dynamics are locally regulated by ECM rigidity together with integrin/ECM association and myosin II contractility. Unlike 2D migration, abrogating contractility stalls 3D migration regardless of ECM pore-size. We find force is not required for clustering of activated integrins on 3D native collagen fibrils. We propose that efficient 3D migration requires local balancing of contractility with ECM stiffness to stabilize adhesions, which facilitates the detachment of activated integrins from ECM fibrils.

Contractility as a global regulator of cellular morphology, velocity, and directionality in low-adhesive fibrillary micro-environments

“…Likewise, also in the 3D setting an increased spreading area as well as a disproportion of pushing and retracting forces might be the reason for the cell elongation observed in the 3D setting. The decrease of velocity in 3D is probably caused by reduced trailing edge retraction as well as altered focal adhesion dynamics [37]. After treatment with calyculin A, cells reacted with both diminished velocity and directionality.…”

Modeling the two-way feedback between contractility and matrix realignment reveals a nonlinear mode of cancer cell invasion

“…For example, the comparison between cell contractility in malignant and normal tissues has shown that the cells with malignant phenotype have a higher level of contractility (1)(2)(3)(4). This elevated contractility is directly proportional to factors such as the stiffness of the extracellular matrix (ECM) and the fiber realignment (5)(6)(7), suggesting that the cross talk between ECM and intracellular contractility mediated by mechanosensory signaling pathways is also implicated in metastasis. Specifically, the activity of Rho, a myosin GTPase that regulates the activity of myosins, is elevated in proportion to the stiffness of the surrounding matrix (1,8,9), and inhibition of Rho-associated protein kinase (ROCK) has been known to reduce the invasiveness of the tumor (1,10), demonstrating that the Rho pathway is a key promoter of cell invasion (11,12).…”

Recent Advances in Engineering the Stem Cell Microniche in 3D

“…Recent efforts have focused on producing collagen materials with tunable properties. By controlling the collagen gelation temperature, collagen hydrogels of different fiber stiffnesses can be prepared 27. Collagen fiber bundling and diameter can be increased by decreasing the gelation temperature, which results in increasing local fiber stiffness.…”