Endosomal signalling via exosome surface TGFβ-1

Ganesh Vilas Shelke,Yanan Yin,Su Chul Jang,Cecilia Lässer,Stefan Wennmalm,Hans Jürgen Hoffmann,Li Li,Yong Song Gho,Jonas Andreas Nilsson,Jan Lötvall

doi:10.1080/20013078.2019.1650458

Abstract

ABSTRACTExtracellular vesicles such as exosomes convey biological messages between cells, either by surface-to-surface interaction or by shuttling of bioactive molecules to a recipient cell’s cytoplasm. Here we show that exosomes released by mast cells harbour both active and latent transforming growth factor β-1 (TGFβ-1) on their surfaces. The latent form of TGFβ-1 is associated with the exosomes via heparinase-II and pH-sensitive elements. These vesicles traffic to the endocytic compartment of recipient human mesenchymal stem cells (MSCs) within 60 min of exposure. Further, the exosomes-associated TGFβ-1 is retained within the endosomal compartments at the time of signalling, which results in prolonged cellular signalling compared to free-TGFβ-1. These exosomes induce a migratory phenotype in primary MSCs involving SMAD-dependent pathways. Our results show that mast cell-derived exosomes are decorated with latent TGFβ-1 and are retained in recipient MSC endosomes, influencing recipient cell migratory phenotype. We conclude that exosomes can convey signalling within endosomes by delivering bioactive surface ligands to this intracellular compartment.

Highlights

Cell-to-cell communication can occur via secreted soluble mediators such as cytokines, bioactive proteins and nucleotides [1,2,3,4]
This study describes in detail how transforming growth factor beta-1 (TGFβ-1) is associated to exosome membranes via heparinase sensitive surface glycans, dissociates from the exosome under acidic conditions, transforms from the latent to the active form, and mediates signalling in endosomes
The exosomes-associated TGFβ-1 is more potent than the free form of the molecule, and we show how exosome-associated TGFβ-1 induces enhanced mesenchymal stem cells (MSCs) cellmigration in vitro via SMAD2 signalling

Summary

Introduction

Cell-to-cell communication can occur via secreted soluble mediators such as cytokines, bioactive proteins and nucleotides [1,2,3,4]. After their release from the cell, they act in an autocrine or paracrine manner to modulate cellular function. To achieve longer half-life, secreted mediators can either exist in an inactive conformation by binding to pro-protein or interact with extracellular matrix proteins, which requires activation before a biological signal can be conveyed [5,6,7]. Inactive TGFβ-1 exists as a dimer of pro-proteins consisting of latent binding protein (LAP) and active-TGFβ-1 subunit. The role of active-TGFβ-1 in activating the SMAD/non-SMAD signalling pathway has been extensively studied [10,11,12]

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Conclusion