(568d) Adhesion-Independent Migration of Monocytes in Viscoelastic Collagen-Based Extracellular Matrices

Circulating monocytes are recruited to tumors, where they can differentiate into macrophages that mediate tumor progression. To reach the tumor microenvironment, monocytes must first extravasate out of the vasculature and migrate through type-1 collagen rich stromal matrix. The viscoelastic stromal matrix around tumors not only stiffens relative to normal stromal matrix, but often exhibits enhanced viscous characteristics, as indicated by faster stress relaxation rate. Stress relaxation refers to a decrease in internal stresses in viscoelastic materials because of applied deformation.

Despite clinically observed changes in matrix properties, the potential impact of changes in matrix stiffness or stress relaxation on monocyte migration is not understood. To address this research gap, we studied how changes in matrix stiffness and viscoelasticity impact the three-dimensional migration of monocytes through stromal-like matrices. Interpenetrating networks (IPNs) of type-1 collagen and alginate, which enable independent tunability of stiffness and stress relaxation over physiologically relevant ranges, were used as confining stromal-like matrices for three-dimensional culture of monocytes.

We find that increased stiffness and faster stress relaxation, independently enhanced the 3D migration of monocytes (Fig. 1). Migrating monocytes have an ellipsoidal or rounded wedge-like morphology, reminiscent of amoeboid migration, with accumulation of actin at the trailing edge. Surprisingly, monocytes migrate independent of matrix adhesion and Rho-mediated contractility but are dependent on actin polymerization and myosin contractility for migration. Our mechanistic studies indicate that actin polymerization at the leading edge generates protrusive forces that generate a path to migrate in the confining viscoelastic matrices. Taken together, our findings implicate matrix stiffness and stress relaxation as key mediators of monocyte migration and reveal an adhesion-independent mode of migration in monocytes.

Implications of study: This study involved the development of stromal-like matrices with independently tunable stiffness and viscoelastic properties using a unique two-temperature gelation strategy. Furthermore, we show that monocytes cells can utilize a previously undescribed mode of migration whereby they push viscoelastic matrix to generate channels through which they can move. This finding highlights the importance of utilizing physiologically relevant materials to study cell migration. More importantly, our data raises the possibility that changes in ECM stiffness and viscoelasticity could determine immune cell recruitment and ultimately shape the immune environment under pathological conditions. Cell recruitment is an important consideration for the development of immune-targeted therapies where preferential recruitment of certain immune cell populations is desired. In addition, the tunable nature of the material developed could enable mechanistic insights into the role of changes in the stromal matrix in the promotion of health and disease.