Cells move in complex three-dimensional (3D) environments in vivo, but most studies focus on migration on uniform 2D surfaces. During 2D migration, the second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and the Rho family guanosine triphosphatases (GTPases) Rac1, Cdc42, and RhoA drive formation of lamellipodia at the leading edge of the cell. However, it is unclear how this translates to the more physiologically relevant 3D environment where cells interact with the extracellular matrix (ECM). Petrie et al. explored how intracellular signaling and differing 3D environments supported distinct modes of cell migration. The authors investigated 3D migration of human foreskin fibroblasts in dermal explants and two in vitro models of the ECM: type I collagen and cell-derived matrix (CDM). In explants, cells formed cylindrical structures called lobopodia and, in contrast to events during 2D migration, active Rac1 was not targeted to the leading edge. This represents a mode of migration in between blebbing and lamellipodial motility (see commentary by Sixt). In the soft, nonlinear elastic environment of 3D collagen, cells formed lamellipodia similarly to the way they are formed during 2D migration. But in stiff, linear elastic 3D CDM, cells formed lobopodia. In 3D collagen, as in 2D migration, PIP3 and active Rac1 and Cdc42 were localized to the leading edge of cells, but in 3D CDM their distribution was not polarized. Knockdown or inhibition of RhoA, its effector ROCK, or its downstream target myosin II switched cells from lobopodial to lamellipodial motility in 3D CDM. The results suggest the existence of two different modes of migration that are controlled by external (elastic properties of the ECM) and internal (RhoA, ROCK, and myosin II signaling) contexts.
- Three Dimensions, Two Modes of Migration
Elastic properties of the extracellular matrix and nonpolarized signaling govern how cells migrate in three-dimensional environments.Permalink: