The role and regulation of blebs in cell migration

Abstract

Blebs are cellular protrusions that have been shown to be instrumental for cell migration in development and disease. Bleb expansion is driven by hydrostatic pressure generated in the cytoplasm by the contractile actomyosin cortex. The mechanisms of bleb formation thus fundamentally differ from the actin polymerization-based mechanisms responsible for lamellipodia expansion. In this review, we summarize recent findings relevant for the mechanics of bleb formation and the underlying molecular pathways. We then review the processes involved in determining the type of protrusion formed by migrating cells, in particular in vivo, in the context of embryonic development. Finally, we discuss how cells utilize blebs for their forward movement in the presence or absence of strong substrate attachment.

Figure 1

Examples of migrating cells forming exclusively blebs, exclusively lamellipodia, switching between protrusion types or forming both protrusion types in combination. Top left: zebrafish PGC expressing a filamentous actin marker (Lifeact-GFP, green) with plasma membranes of all cells labeled in red (mCherry-F globin); image courtesy J. Bandemer. Scale bar: 5 μm. Top right: HL60 cell expressing Lifeact-GFP; image courtesy K. Wilson and G. Charras. Scale bar: 10 μm. Bottom left: Walker carcinosarcoma cells expressing Lifeact-GFP. Cells are selected for (lamellipodia forming) or against (bleb-forming) adhesion [28^••]; image courtesy M. Bergert. Scale bars: 10 μm. Bottom right: zebrafish mesendoderm progenitor cell expressing a plasma membrane marker (GPI-RFP, red and Lifeact-GFP, green); courtesy A. Diz-Muñoz. Scale bar: 10 μm.

Figure 2

Parameters contributing to bleb formation. Cells whose actin cortex is intact, whose level of cortex–membrane linker proteins is high and which have low intracellular pressure do not form blebs (left cell). Affecting each of the three parameters alone is typically insufficient for the generation of blebs (cells in middle). Blebbing cells are characterized by high myosin-dependent contractility that increases the intracellular pressure, reduced level of linker proteins and/or breaks in the actin cortex at the region where the bleb forms (right cell).

Figure 3

Mechanisms of force transduction in bleb-based migration. Cells can generate traction and move forward by adhering to cells in their environment through cell–cell adhesion or cell–extracellular matrix in three-dimensional or two-dimensional environments (a and b) respectively, depicted for cell–cell adhesion, with the arrows indicating actin retrograde flow, or by generating hydrostatic pressure and pressing against cells or structures in their environment (chimneying) (c), arrows indicate pushing forces.