Matrix degradability controls multicellularity of 3D cell migration

Abstract

A major challenge in tissue engineering is the development of materials that can support angiogenesis, wherein endothelial cells from existing vasculature invade the surrounding matrix to form new vascular structures. To identify material properties that impact angiogenesis, here we have developed an in vitro model whereby molded tubular channels inside a synthetic hydrogel are seeded with endothelial cells and subjected to chemokine gradients within a microfluidic device. To accomplish precision molding of hydrogels and successful integration with microfluidics, we developed a class of hydrogels that could be macromolded and micromolded with high shape and size fidelity by eliminating swelling after polymerization. Using this material, we demonstrate that matrix degradability switches three-dimensional endothelial cell invasion between two distinct modes: single-cell migration and the multicellular, strand-like invasion required for angiogenesis. The ability to incorporate these tunable hydrogels into geometrically constrained settings will enable a wide range of previously inaccessible biomedical applications.

Spheroids of Endothelial Cells and Vascular Smooth Muscle Cells Promote Cell Migration in Hyaluronic Acid and Fibrinogen Composite Hydrogels

“…Although the 3D biomaterials have been extensively studied in terms of influences on cell morphology, polarization, and differentiation, little attention has been paid to their effect on cell migration. Trappmann et al studied the behaviors of cells in 3D tubular materials with different degradation properties to explore the conditions for the formation of vascularization [67]. In addition, the collective cell migration is more beneficial to the study of cell-cell interactions compared to the traditional single-cell migration [55].…”

Deciphering the relative roles of matrix metalloproteinase‐ and plasmin‐mediated matrix degradation during capillary morphogenesis using engineered hydrogels

“…Our model also provides a tool to investigate matrix remodeling in organotypic capillary morphogenesis with specific EC and stromal cell combinations. Finally, the unique matrix‐centric perspective of these studies provides strong evidence to justify the preferential selection of MMP‐degradable peptide crosslinkers in synthetic hydrogels used to study vascular morphogenesis and promote vascularization.…”

Three-dimensional traction microscopy accounting for cell-induced matrix degradation

“…Since cells secrete enzymes (e.g., MMPs) that can locally degrade the ECM [21,22], we assume that the two Lamé parameters are nonuniform across the degraded ECM. This effect can be represented by a degradation parameter d(x) (0 ≤ d < 1), so that…”

“…Most 3DTM approaches have assumed that the ECM has spatially uniform mechanical properties, which are typically measured by standard techniques such as bulk rheometry [18], indentation testing [19], and atomic force microscopy [20] prior to the encapsulation of the cell. However, since cells express enzymes (e.g., matrix metalloproteinase (MMP)) that can locally degrade the ECM [21,22,23,24,25], the assumption of uniform mechanical properties is questionable and is likely to introduce inaccuracies in estimating tractions. In particular, experimental studies have highlighted the importance of incorporating ECM heterogeneity in measuring stresses within the ECM [26,27].…”