Secretome and Tunneling Nanotubes: A Multilevel Network for Long Range Intercellular Communication between Endothelial Cells and Distant Cells

Abstract

As a cellular interface between the blood and tissues, the endothelial cell (EC) monolayer is involved in the control of key functions including vascular tone, permeability and homeostasis, leucocyte trafficking and hemostasis. EC regulatory functions require long-distance communications between ECs, circulating hematopoietic cells and other vascular cells for efficient adjusting thrombosis, angiogenesis, inflammation, infection and immunity. This intercellular crosstalk operates through the extracellular space and is orchestrated in part by the secretory pathway and the exocytosis of Weibel Palade Bodies (WPBs), secretory granules and extracellular vesicles (EVs). WPBs and secretory granules allow both immediate release and regulated exocytosis of messengers such as cytokines, chemokines, extracellular membrane proteins, coagulation or growth factors. The ectodomain shedding of transmembrane protein further provide the release of both receptor and ligands with key regulatory activities on target cells. Thin tubular membranous channels termed tunneling nanotubes (TNTs) may also connect EC with distant cells. EVs, in particular exosomes, and TNTs may contain and transfer different biomolecules (e.g., signaling mediators, proteins, lipids, and microRNAs) or pathogens and have emerged as a major triggers of horizontal intercellular transfer of information.

Keywords: chemokines; cytokines; ectodomain shedding; endothelial cells; exosomes; extracellular vesicles; intercellular communication; secretome; secretory pathway; tunneling nanotubes.

Figure 1

A schematic overview of secretory granules and extracellular vesicles and their cargoes in endothelial cells.

Figure 2

A schematic overview of TNT major characteristics and cargoes. Conditions inducing TNT formation and molecules implicated in TNT biogenesis are indicated.

Figure 3

A representative confocal imaging of TNT between two endothelial cells. CoImmunostaining for F-actin (red) and MHC class I molecules (green) on human aortic EC culture. Nuclei are staining with DAPI (blue) and costainings are visualized as superimposition of images (magnification: 600×).