Trans-cellular migration: cell-cell contacts get intimate

Abstract

Trans-cellular migration, the movement of one cell directly through another, seems an unlikely, counterintuitive, and even bizarre process. Trans-cellular migration has been reported for nearly half a century in leukocyte transendothelial migration in vivo, but is not well enough accepted to widely feature in textbook accounts of diapedesis. Recently, the first in vitro and additional in vivo observations of trans-cellular diapedesis have been reported. Mechanisms by which this occurs are just beginning to be elucidated and point to podosome-like protrusive activities in leukocytes and specific fusogenic functions in endothelial cells. Emerging evidence for a quantitatively significant contribution of trans-cellular migration to leukocyte trafficking in increasingly diverse settings suggests that this phenomenon represents an important and physiologic cell biological process.

Figure 1

Mechanisms for trans-cellular diapedesis. (a) Stages of extravasation. Leukocytes (green) entering a postcapillary venule (purple) initially undergo transient rolling type interactions mediated predominantly by selectins. This facilitates chemokine-dependent activation and firm arrest mediated by leukocyte integrins (e.g. LFA-1, Mac1, and VLA-4) binding to endothelial cell adhesion molecules (e.g. ICAM-1/2 and VCAM-1). Subsequently leukocytes migrate laterally over the surface of the endothelium probing for a site to penetrate the endothelium. Finally leukocytes cross the endothelial barrier (i.e. diapedese) and enter the intersitium (tan) by migrating either directly through individual endothelial cells via a trans-cellular pore or between them via a para-cellular gap. Two individual endothelial cells are highlighted (blue and red) and depicted in expanded views during initiation of trans-cellular diapedesis in (b)–(d). (b) Podosome probing. The schematic depicts a ‘snapshot’ of a lymphocyte laterally migrating toward an intact interendothelial junction (see ultrastructure in (e)). Locations where specific junctional adhesion complexes, including tight (yellow), gap (green), and adherens (orange) junctions, form are indicated. During migration dozens of actin (red)-dependent podosome-like protrusions dynamically form and retract, concomitantly forcing endothelial invaginations termed ‘podo-prints’ (see ultrastructure in (f)). Endothelial vesicles, VVO, and caveolae are seen enriched near or directly fused to podo-prints. Fusogenic proteins (i.e. SNAREs) also accumulate at such sites. This dynamic protrusion behavior is thought serve in migratory pathfinding as a means of ‘probing’ or ‘palpating’ the endothelial surface for sites permissive to trans-cellular diapedesis. (c) Transmigratory cup formation. Overlapping temporally with podosome palpation (b), endothelial cells proactively protrude actin/intermediate filament-dependent, ICAM-1/VCAM-1-enrhiched protrusions (*) that embrace adherent leukocytes, forming ‘transmigratory cups’ that are thought to facilitate transition from lateral to transendothelial migration. (d) Trans-cellular pore formation. At permissive sites podosome-like protrusions progressively extend, transitioning to ‘invasive podosomes’, to initiate trans-cellular pore formation for diapedesis (see ultrastructure in (g)). Active SNARE complex-dependent endothelial vesicle fusion at the site of protrusion may facilitate this process. (e) Electron micrograph of a mouse skin postcapillary venule interendothelial junction. Note the highly interdigitated interface. A density toward the top of the interface probably represents a tight junction. Other junctional adhesion complexes cannot be identified unambiguously in this micrograph and are therefore not specifically indicated. Significant amounts of vesicles, VVO, and caveolae are also present. (f) Electron micrographs depicting representative lymphocyte podosome-like protrusions forcing podo-print invaginations into the endothelial surface. Significant levels of endothelial vesicles and caveolea are evident near these protrusions both free in the cytoplasm and fused to the podo-prints (red arrows). (g) Electron micrographs depicting representative lymphocyte invasive podosomes spanning across the majority of the endothelial thickness and forcing endothelial apical and basal membranes into close opposition, as though poised for trans-cellular pore formation. Electron micrographs were provided by Tracey Sciuto and Ann Dvorak.