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.

Advances in Endothelial Cell Biology: From Knowledge to Control

“…ECs possess a multilevel machinery to deliver messages to distant cells such as cells circulating in the blood vessel including platelets, leucocytes, other vascular cells, or normal and tumor cells in tissues. The secretory pathways, granules, extracellular vesicles, generating the endothelial secretome, and tunneling nanotubes (TNTs) used for intercellular communication between ECs and distant cells are also reviewed [ 18 ]. Efficient for adjusting thrombosis, angiogenesis, inflammation, infection, and immunity, these processes may also provide future therapeutic and diagnostic tools.…”

Endothelial Secretome

“…Exchange information at a distance with other ECs, and with other blood cells, with the circulating hematopoietic stem cells. Vascular ECs crosstalk is intermediated by the secretory vesicles and granules with the purpose to maintain vascular homeostasis and integrity [4].…”

“…Several regulator molecules localized simultaneously on the EVs surface, and on the EC acceptor cells are known to be implicated in the delivery of cargo and uptake into the target cell, including integrins and integrin-associated proteins, tetraspanins, T-cell immunoglobulin, and mucin domain-containing protein-4 (TIM4), and lectins and heparan sulfate proteoglycans [4]. Tim4 is a receptor for TIM1 and phosphatidylserine on apoptotic cells.…”

“…Without Tim4, macrophages cannot phagocytose apoptotic cells. These molecular pairs convey cargo delivery specifically to the vascular recipient cells, although it is not entirely clear how these processes occur [4].…”

“…EVs transfer their cargo from the parent cell to the target cell by: (1) docking to the target cell, (2) internalization of the EVs, and intracellular sorting through one of the endocytotic pathways; a pool of internalized EVs by the acceptor (target) cells are sent via endosomal escape, and (3) transfer of the EV content to the acceptor cell [4]. This way EVs influence the phenotypic traits of the recipient cell.…”