Nonpolarized signaling reveals two distinct modes of 3D cell migration
Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA.The Journal of Cell Biology (Impact Factor: 9.83). 04/2012; 197(3):439-55. DOI: 10.1083/jcb.201201124
We search in this paper for context-specific modes of three-dimensional (3D) cell migration using imaging for phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and active Rac1 and Cdc42 in primary fibroblasts migrating within different 3D environments. In 3D collagen, PIP3 and active Rac1 and Cdc42 were targeted to the leading edge, consistent with lamellipodia-based migration. In contrast, elongated cells migrating inside dermal explants and the cell-derived matrix (CDM) formed blunt, cylindrical protrusions, termed lobopodia, and Rac1, Cdc42, and PIP3 signaling was nonpolarized. Reducing RhoA, Rho-associated protein kinase (ROCK), or myosin II activity switched the cells to lamellipodia-based 3D migration. These modes of 3D migration were regulated by matrix physical properties. Specifically, experimentally modifying the elasticity of the CDM or collagen gels established that nonlinear elasticity supported lamellipodia-based migration, whereas linear elasticity switched cells to lobopodia-based migration. Thus, the relative polarization of intracellular signaling identifies two distinct modes of 3D cell migration governed intrinsically by RhoA, ROCK, and myosin II and extrinsically by the elastic behavior of the 3D extracellular matrix.
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[Show abstract] [Hide abstract] ABSTRACT: Cells migrate through 3D environments using a surprisingly wide variety of molecular mechanisms. These distinct modes of migration often rely on the same intracellular components, which are used in different ways to achieve cell motility. Recent work reveals that how a cell moves can be dictated by the relative amounts of cell-matrix adhesion and actomyosin contractility. A current concept is that the level of difficulty in squeezing the nucleus through a confining 3D environment determines the amounts of adhesion and contractility required for cell motility. Ultimately, determining how the nucleus controls the mode of cell migration will be essential for understanding both physiological and pathological processes dependent on cell migration in the body.
- "Determining how a single cell can transition between two or more migration modes will help us to understand how these processes are related mechanistically . For example, treatment of primary human fibroblasts with platelet-derived growth factor (PDGF) is sufficient to trigger high-pressure lobopodial migration (Figure 1a) in a cross-linked 3D matrix . Inhibiting actomyosin contractility switches these cells to the less efficient Rac1-mediated, lamellipodial migration mechanism (Figure 1b ). "
[Show abstract] [Hide abstract] ABSTRACT: Mesenchymal precursors (MPs) present some advantageous features, such as differentiation and migration, which make them promising candidates for cell therapy. A better understanding of MP migration characteristics would aid the development of cell delivery protocols. Traditionally, cell migration is thought to occur only through the formation of lamellipodia. More recently, contractility-driven bleb formation has emerged as an alternative mechanism of motility. Here we report that MPs derived from different tissues present spontaneously dynamic cytoplasmic projections in sub-confluent culture, which appear as a combination of lamellipodia with blebs in the leading edge. Upon initial seeding, however, only bleb structures could be observed. Immunofluorescence revealed the presence of pERM, RhoA and F-actin during the blebbing process. Results from migration assays in the presence of blebbistatin, a myosin II inhibitor, showed that bleb formation correlated with migratory capacity, suggesting a functional role for blebs in migration. Bleb formation might be a useful mechanism to improve cell migration in cellular therapy protocols.
- "Interestingly, blebbistatin appears to have a greater effect on the blebbing process in newly-seeded cells rather than cultured cells, suggesting that blebs are fundamental for cell adhesion; in fact, cells suffer a delay in elongation and remain rounded for longer periods of time. Previous studies have reported that substrate adhesiveness affects the formation of blebs [22,23] . Usually migration through blebbing occurs in confined and non-adhesive environ- ments2829303132 . "
[Show abstract] [Hide abstract] ABSTRACT: Cell membrane shape changes are important for many aspects of normal biological function, such as tissue development, wound healing and cell division and motility. Various disease states are associated with deregulation of how cells move and change shape, including notably tumor initiation and cancer cell metastasis. Cell motility is powered, in large part, by the controlled assembly and disassembly of the actin cytoskeleton. Much of this dynamic happens in close proximity to the plasma membrane due to the fact that actin assembly factors are membrane-bound, and thus actin filaments are generally oriented such that their growth occurs against or near the membrane. For a long time, the membrane was viewed as a relatively passive scaffold for signaling. However, results from the last five years show that this is not the whole picture, and that the dynamics of the actin cytoskeleton are intimately linked to the mechanics of the cell membrane. In this review, we summarize recent findings concerning the role of plasma membrane mechanics in cell cytoskeleton dynamics and architecture, showing that the cell membrane is not just an envelope or a barrier for actin assembly, but is a master regulator controlling cytoskeleton dynamics and cell polarity.
- "The protrusion thus produced can be used by the cell to pull itself forward, particularly in confined environments . Lamellipodia (polymerization-based) and blebs (contraction-based) can co-exist, or combine to give hybrid modes such as the lobopodia . The close association of the actin cytoskeleton and the cell membrane means that the membrane could affect the cytoskeleton for purely mechanical reasons, unrelated to the role of the membrane in biochemical signaling cascades. "