A functional corona around extracellular vesicles enhances angiogenesis, skin regeneration and immunomodulation

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Abstract

Nanoparticles can acquire a plasma protein corona defining their biological identity. Corona functions were previously considered for cell‐derived extracellular vesicles (EVs). Here we demonstrate that nano‐sized EVs from therapy‐grade human placental‐expanded (PLX) stromal cells are surrounded by an imageable and functional protein corona when enriched with permissive technology. Scalable EV separation from cell‐secreted soluble factors via tangential flow‐filtration (TFF) and subtractive tandem mass‐tag (TMT) proteomics revealed significant enrichment of predominantly immunomodulatory and proangiogenic proteins. Western blot, calcein‐based flow cytometry, super‐resolution and electron microscopy verified EV identity. PLX‐EVs partly protected corona proteins from protease digestion. EVs significantly ameliorated human skin regeneration and angiogenesis in vivo, induced differential signalling in immune cells, and dose‐dependently inhibited T cell proliferation in vitro. Corona removal by size‐exclusion or ultracentrifugation abrogated angiogenesis. Re‐establishing an artificial corona by cloaking EVs with fluorescent albumin as a model protein or defined proangiogenic factors was depicted by super‐resolution microscopy, electron microscopy and zeta‐potential shift, and served as a proof‐of‐concept. Understanding EV corona formation will improve rational EV‐inspired nano‐therapy design.

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Most cited references 49

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Is Open Access

Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

Clotilde Théry, Kenneth W Witwer, Elena Aikawa … (2020)

ABSTRACT The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.

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Efficient analysis of very large amounts of raw data for peptide identification and protein quantification is a principal challenge in mass spectrometry (MS)-based proteomics. Here we describe MaxQuant, an integrated suite of algorithms specifically developed for high-resolution, quantitative MS data. Using correlation analysis and graph theory, MaxQuant detects peaks, isotope clusters and stable amino acid isotope-labeled (SILAC) peptide pairs as three-dimensional objects in m/z, elution time and signal intensity space. By integrating multiple mass measurements and correcting for linear and nonlinear mass offsets, we achieve mass accuracy in the p.p.b. range, a sixfold increase over standard techniques. We increase the proportion of identified fragmentation spectra to 73% for SILAC peptide pairs via unambiguous assignment of isotope and missed-cleavage state and individual mass precision. MaxQuant automatically quantifies several hundred thousand peptides per SILAC-proteome experiment and allows statistically robust identification and quantification of >4,000 proteins in mammalian cell lysates.

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The biology, function, and biomedical applications of exosomes

Raghu Kalluri, Valerie LeBleu (2020)

The study of extracellular vesicles (EVs) has the potential to identify unknown cellular and molecular mechanisms in intercellular communication and in organ homeostasis and disease. Exosomes, with an average diameter of ~100 nanometers, are a subset of EVs. The biogenesis of exosomes involves their origin in endosomes, and subsequent interactions with other intracellular vesicles and organelles generate the final content of the exosomes. Their diverse constituents include nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their cell of origin. In various diseases, exosomes offer a window into altered cellular or tissue states, and their detection in biological fluids potentially offers a multicomponent diagnostic readout. The efficient exchange of cellular components through exosomes can inform their applied use in designing exosome-based therapeutics.

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Author and article information

Contributors

Dirk Strunk: dirk.strunk@pmu.ac.at

Journal

Journal ID (nlm-ta): J Extracell Vesicles

Journal ID (iso-abbrev): J Extracell Vesicles

Journal ID (doi): 10.1002/(ISSN)2001-3078

Journal ID (publisher-id): JEV2

Title: Journal of Extracellular Vesicles

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Electronic): 2001-3078

Publication date (Electronic): 09 April 2022

Publication date (Print): April 2022

Volume: 11

Issue: 4 ( doiID: 10.1002/jev2.v11.4 )

Electronic Location Identifier: e12207

Affiliations

[ ¹ ] Cell Therapy Institute Spinal Cord Injury and Tissue Regeneration Centre Salzburg (SCI‐TReCS) Paracelsus Medical University (PMU) Salzburg Austria

[ ² ] Department of Biosciences Paris Lodron University Salzburg Salzburg Austria

[ ³ ] Department of Transfusion Medicine and SCI‐TReCS PMU Salzburg Austria

[ ⁴ ] Core Facility Flow Cytometry and Department of Surgery Research Laboratories Medical University of Vienna Vienna Austria

[ ⁵ ] Vienna Biocentre Core Facilities Vienna Austria

[ ⁶ ] Pluristem Ltd. Haifa Israel

[ ⁷ ] Berlin Institute of Health at Charité – Universitätsmedizin BIH Centre for Regenerative Therapies (BCRT) Berlin Germany

Author notes

[*] [* ] Correspondence

Dirk Strunk, Cell Therapy Institute, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI‐TReCS), Paracelsus Medical University (PMU), Salzburg, Austria.

Email dirk.strunk@ 123456pmu.ac.at

Author information

Martin Wolf https://orcid.org/0000-0002-4795-8086

Article

Publisher ID: JEV212207

DOI: 10.1002/jev2.12207

PMC ID: 8994701

PubMed ID: 35398993

SO-VID: bb6ab8b8-b382-4b85-b6d0-2b437feda29b

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date revision received : 08 February 2022

Date received : 01 October 2021

Date accepted : 02 March 2022

Page count

Figures: 8, Tables: 1, Pages: 20, Words: 12387

Funding

Funded by: Land Salzburg

Award ID: 20102‐F2100572‐FPREV‐Quant

Award ID: IWB/EFRE P1812596

Award ID: WISS 2025 20102‐F1900731‐KZP EV‐TT

Award ID: F2000237‐FIPSTEBS

Funded by: Austrian Science Fund , doi 10.13039/501100002428;

Award ID: W1213

Funded by: European Commission , doi 10.13039/501100000780;

Award ID: 731377

Award ID: 733006

Funded by: F 2000237‐FIP “STEBS”

Custom metadata

source-schema-version-number 2.0

cover-date April 2022

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.3 mode:remove_FC converted:09.04.2022

Keywords: angiogenesis,ev corona,ev function,extracelular vesicle,placenta derived stromal cells,tangential flow filtration

Data availability:

Keywords: angiogenesis, ev corona, ev function, extracelular vesicle, placenta derived stromal cells, tangential flow filtration

A functional corona around extracellular vesicles enhances angiogenesis, skin regeneration and immunomodulation

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