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Challenges and directions in studying cell–cell communication by extracellular vesicles

Nature Reviews Molecular Cell Biology volume 23, pages 369–382 (2022)Cite this article

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Abstract

Extracellular vesicles (EVs) are increasingly recognized as important mediators of intercellular communication. They have important roles in numerous physiological and pathological processes, and show considerable promise as novel biomarkers of disease, as therapeutic agents and as drug delivery vehicles. Intriguingly, however, understanding of the cellular and molecular mechanisms that govern the many observed functions of EVs remains far from comprehensive, at least partly due to technical challenges in working with these small messengers. Here, we highlight areas of consensus as well as contentious issues in our understanding of the intracellular and intercellular journey of EVs: from biogenesis, release and dynamics in the extracellular space, to interaction with and uptake by recipient cells. We define knowledge gaps, identify key questions and challenges, and make recommendations on how to address these.

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Fig. 1: State of the art of EV biogenesis and dissemination in the extracellular space.
Fig. 2: The dynamics of EVs in extracellular space leading to their uptake and functions in recipient cells.
Fig. 3: Key questions and challenges in studying EV biology.

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Acknowledgements

The work of G.v.N. and A.C. is supported by proEVLifeCycle funded by the European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement No. 860303. The work of G.v.N. is also supported by the Fondation ARC (#PGA1RF20190208474). D.R.F.C. was supported by the BBSRC (BB/P006205/1). G.R. is supported by Fondation pour la Recherche Medicale Espoirs de la Recherche (FRM 2020-2023), CNRS and Institut Curie. P.V. acknowledges support from the European Research Council (ERC) (ERC Starting grant OBSERVE #851936) and the Netherlands Organization for Scientific Research (NWO) (NWO Vidi grant #18367).

Author information

Authors and Affiliations

  1. Université de Paris, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Paris, France

    Guillaume van Niel

  2. GHU Paris Psychiatrie et Neurosciences, Hôpital Sainte Anne, Paris, France

    Guillaume van Niel

  3. Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK

    David R. F. Carter

  4. Evox Therapeutics Limited, Oxford Science Park, Oxford, UK

    David R. F. Carter

  5. Division of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, UK

    Aled Clayton

  6. School of Clinical Dentistry, The University of Sheffield, Sheffield, UK

    Daniel W. Lambert

  7. Neuroscience Institute, The University of Sheffield, Sheffield, UK

    Daniel W. Lambert

  8. Healthy Lifespan Institute, The University of Sheffield, Sheffield, UK

    Daniel W. Lambert

  9. Institut Curie, PSL Research University, CNRS, UMR144, Paris, France

    Graça Raposo

  10. Institut Curie, PSL Research University, CNRS, UMR144, Cell and Tissue Imaging Facility (PICT-IBiSA), Paris, France

    Graça Raposo

  11. CDL Research, University Medical Center Utrecht, Utrecht, Netherlands

    Pieter Vader

  12. Department of Experimental Cardiology, University Medical Center Utrecht, Utrecht, Netherlands

    Pieter Vader

Authors
  1. Guillaume van Niel
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  2. David R. F. Carter
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  3. Aled Clayton
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  4. Daniel W. Lambert
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  5. Graça Raposo
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  6. Pieter Vader
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Contributions

The authors contributed equally to all aspects of the article. G.v.N. designed the figures.

Corresponding authors

Correspondence to Guillaume van Niel or Pieter Vader.

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Competing interests

D.R.F.C. is an employee of Evox Therapeutics. P.V. serves on the scientific advisory board of Evox Therapeutics. The other authors declare no competing interests.

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Nature Reviews Molecular Cell Biology thanks An Hendrix and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

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Glossary

Oncosomes

Large extracellular vesicles generated from the plasma membrane of cancer cells.

ESCRT machinery

Protein machinery composed of several multiprotein subcomplexes that enable membrane remodelling at endosomes, plasma membrane or nuclear envelope resulting in membrane budding.

Syntenin–Alix pathway

Alternative sorting mechanism at endosomes to generate intraluminal vesicles that shortcuts the first subunits of the ESCRT machinery.

Tetraspanins

Family of transmembrane proteins that are enriched in various subtypes of extracellular vesicles and are characterized by their capacity to associate into dynamic membrane microdomains.

Arrestin domain-containing protein 1

(ARRDC1). Protein adaptor for the NEDD4 family of ubiquitin ligases that is involved in the generation of extracellular vesicles at the plasma membrane.

MHC II

Transmembrane protein heterocomplex expressed by antigen-presenting cells that present antigenic peptides to T cell receptors.

Syndecan

Single transmembrane domain protein that is thought to act as co-receptor, especially for G protein-coupled receptors, and is known to engage the syntenin–Alix pathway for sorting to exosomes.

Microautophagy

Sorting process occurring at the late endosome or lysosome to engulf cytoplasm and cytosolic proteins into intraluminal vesicles.

Processing bodies

Distinct foci consisting of many enzymes and nucleic acids, formed by phase separation within the cytoplasm of the eukaryotic cell and primarily involved in mRNA turnover.

Retraction fibres

Membrane-elongated structures generated at the rear of migratory cells connecting the adhesion pattern to the round cell body.

Amphisomes

Chimeric organelle resulting from the fusion of autophagosomes and multivesicular endosomes.

Macroautophagy

Intracellular process leading to the specific enwrapping of cytosolic material and organelles by membranes to target them to lysosomes for degradation.

Filopodia

Cytoplasmic projections that extend beyond the leading edge of migrating cells.

Microvilli

Membrane protrusions, primarily generated in epithelia, involved in absorption, secretion and adhesion.

Nanotubes

Membrane-elongated structures connecting two cells.

Glycocalyx

Set of glycolipids and glycoproteins present on the extracellular surface.

BAR domain

Highly conserved protein dimerization domain displaying a banana shape that preferentially binds to curved membranes and sustains membrane deformation and traffic.

Ceramide

Sphingolipid that induces inward budding of endosomes to produce intraluminal vesicles in an ESCRT-independent manner.

Matrix vesicles

(MVs). Extracellular spherical bodies selectively located in the pre-mineralized matrix of cartilage, bone and dentin.

Proteoglycan

A family of ubiquitous, heavily glycosylated proteins that function as critical components of the extracellular matrix.

Tetherin

Lipid raft-associated integral membrane protein that tethers virus-like particles and exosomes, thereby inhibiting them from discharging into the extracellular milieu.

Lysyl oxidase

(LOX). Enzyme that induces crosslinking of extracellular matrix proteins by converting lysine molecules into highly reactive aldehydes.

Transglutaminase

(TG). Enzyme that induces crosslinking of extracellular matrix proteins by generating isopeptide bonds.

Invadopodia

Specialized actin-rich membrane protrusions that concentrate high proteolytic activities and are capable of crossing extracellular barriers.

Integumentary system

Organ system forming the outermost layer of an animal’s body and includes skin, hair, nails and exocrine glands.

Phosphatidylserine

(PS). Phospholipid commonly found in the inner leaflet of biological membranes, which gets exposed on the surface of apoptotic cells and is used by viruses and extracellular vesicles to enter cells via apoptotic mimicry.

Complement

System of plasma proteins that, upon activation, leads to opsonization and engulfment of pathogens as part of the innate immune system.

Macropinocytosis

Regulated form of endocytosis that involves non-selective uptake of extracellular material.

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van Niel, G., Carter, D.R.F., Clayton, A. et al. Challenges and directions in studying cell–cell communication by extracellular vesicles. Nat Rev Mol Cell Biol 23, 369–382 (2022). https://doi.org/10.1038/s41580-022-00460-3

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