Defining mesenchymal stromal cell (MSC)-derived small extracellular vesicles for therapeutic applications

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ABSTRACT

Small extracellular vesicles (sEVs) from mesenchymal stromal/stem cells (MSCs) are transiting rapidly towards clinical applications. However, discrepancies and controversies about the biology, functions, and potency of MSC-sEVs have arisen due to several factors: the diversity of MSCs and their preparation; various methods of sEV production and separation; a lack of standardized quality assurance assays; and limited reproducibility of in vitro and in vivo functional assays. To address these issues, members of four societies (SOCRATES, ISEV, ISCT and ISBT) propose specific harmonization criteria for MSC-sEVs to facilitate data sharing and comparison, which should help to advance the field towards clinical applications. Specifically, MSC-sEVs should be defined by quantifiable metrics to identify the cellular origin of the sEVs in a preparation, presence of lipid-membrane vesicles, and the degree of physical and biochemical integrity of the vesicles. For practical purposes, new MSC-sEV preparations might also be measured against a well-characterized MSC-sEV biological reference. The ultimate goal of developing these metrics is to map aspects of MSC-sEV biology and therapeutic potency onto quantifiable features of each preparation.

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Most cited references 28

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Mast cell- and dendritic cell-derived exosomes display a specific lipid composition and an unusual membrane organization.

Karine Laulagnier, Claude Motta, Safouane Hamdi … (2004)

Exosomes are small vesicles secreted from multivesicular bodies, which are able to stimulate the immune system leading to tumour cell eradication. We have analysed lipids of exosomes secreted either upon stimulation from rat mast cells (RBL-2H3 cells), or constitutively from human dendritic cells. As compared with parent cells, exosomes displayed an enrichment in sphingomyelin, but not in cholesterol. Phosphatidylcholine content was decreased, but an enrichment was noted in disaturated molecular species as in phosphatidylethanolamines. Lyso(bis)phosphatidic acid was not enriched in exosomes as compared with cells. Fluorescence anisotropy demonstrated an increase in exosome-membrane rigidity from pH 5 to 7, suggesting their membrane reorganization between the acidic multivesicular body compartment and the neutral outer cell medium. NMR analysis established a bilayer organization of exosome membrane, and ESR studies using 16-doxyl stearic acid demonstrated a higher flip-flop of lipids between the two leaflets as compared with plasma membrane. In addition, the exosome membrane exhibited no asymmetrical distribution of phosphatidylethanolamines. Therefore exosome membrane displays a similar content of the major phospholipids and cholesterol, and is organized as a lipid bilayer with a random distribution of phosphatidylethanolamines. In addition, we observed tight lipid packing at neutral pH and a rapid flip-flop between the two leaflets of exosome membranes. These parameters could be used as a hallmark of exosomes.

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Mesenchymal stem cell exosomes.

Ruenn Chai Lai, Ronne Yeo, Sai Lim (2015)

MSCs are an extensively used cell type in clinical trials today. The initial rationale for their clinical testing was based on their differentiation potential. However, the lack of correlation between functional improvement and cell engraftment or differentiation at the site of injury has led to the proposal that MSCs exert their effects not through their differentiation potential but through their secreted product, more specifically, exosomes, a type of extracellular vesicle. We propose here that MSC exosomes function as an extension of MSC's biological role as tissue stromal support cells. Like their cell source, MSC exosomes help maintain tissue homeostasis for optimal tissue function. They target housekeeping biological processes that operate ubiquitously in all tissues and are critical in maintaining tissue homeostasis, enabling cells to recover critical cellular functions and begin repair and regeneration. This hypothesis provides a rationale for the therapeutic efficacy of MSCs and their secreted exosomes in a wide spectrum of diseases. Here, we give a brief introduction of the biogenesis of MSC exosomes, review their physiological functions and highlight some of their biochemical potential to illustrate how MSC exosomes could restore tissue homeostasis leading to tissue recovery and repair.

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Molecular lipidomics of exosomes released by PC-3 prostate cancer cells.

Ilpo Vattulainen, Tuulia Sylvänne, Alicia Llorente … (2013)

The molecular lipid composition of exosomes is largely unknown. In this study, sophisticated shotgun and targeted molecular lipidomic assays were performed for in-depth analysis of the lipidomes of the metastatic prostate cancer cell line, PC-3, and their released exosomes. This study, based in the quantification of approximately 280 molecular lipid species, provides the most extensive lipid analysis of cells and exosomes to date. Interestingly, major differences were found in the lipid composition of exosomes compared to parent cells. Exosomes show a remarkable enrichment of distinct lipids, demonstrating an extraordinary discrimination of lipids sorted into these microvesicles. In particular, exosomes are highly enriched in glycosphingolipids, sphingomyelin, cholesterol, and phosphatidylserine (mol% of total lipids). Furthermore, lipid species, even of classes not enriched in exosomes, were selectively included in exosomes. Finally, it was found that there is an 8.4-fold enrichment of lipids per mg of protein in exosomes. The detailed lipid composition provided in this study may be useful to understand the mechanism of exosome formation, release and function. Several of the lipids enriched in exosomes could potentially be used as cancer biomarkers.

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Author and article information

Journal

Journal ID (nlm-ta): J Extracell Vesicles

Journal ID (iso-abbrev): J Extracell Vesicles

Journal ID (publisher-id): ZJEV

Journal ID (publisher-id): zjev20

Title: Journal of Extracellular Vesicles

Publisher: Taylor & Francis

ISSN (Electronic): 2001-3078

Publication date Collection: 2019

Publication date (Electronic): 29 April 2019

Volume: 8

Issue: 1

Electronic Location Identifier: 1609206

Affiliations

[a ]Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine , Baltimore, MD, USA

[b ]Department of Neurology, The Johns Hopkins University School of Medicine , Baltimore, MD, USA

[c ]Division Internal Medicine and Dermatology, Nephrology and Hypertension, University Medical Center Utrecht , Utrecht, The Netherlands

[d ]Department of Medical Sciences and Molecular Biotechnology Center, University of Torino , Torino, Italy

[e ]Bioprocessing Technology Institute, Agency for Science, Technology and Research , Singapore, Singapore

[f ]MAB Laboratory, TPM of Mirandola , Mirandola, Italy

[g ]Division of Oncology, University of Modena and Reggio Emilia , Modena, Italy

[h ]GMP Laboratory, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Research Program Nanovesicular Therapies, Department of Transfusion Medicine and Celericon Therapeutics G.m.b.H., Paracelsus Medical University (PMU) , Salzburg, Austria

[i ]Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University , Bundoora, Australia

[j ]Department of Vascular Surgery, University Medical Center Utrecht , Utrecht, The Netherlands

[k ]Department of Haematology, St George’s University Hospital NHS Trust , London, UK

[l ]Cell Therapy Facility, Blood Services Group Health Sciences Authority , Singapore, Singapore

[m ]Institute of Medical Biology, Agency for Science, Technology and Research , Singapore, Singapore

[n ]Department of Pediatrics, Harvard Medical School & Division of Newborn Medicine, Boston Children’s Hospital , Boston, MA, USA

[o ]Division of Environmental and Occupational Medicine, Department of Environmental and Occupational Health, Graduate School of Public Health at the University of Pittsburgh , Pittsburgh, PA, USA

[p ]Department of Tissue Regeneration Science and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University , Kyoto, Japan

[q ]Faculty of Dentistry, National University of Singapore , Singapore, Singapore

[r ]Health Sciences Research Facility, University of Vermont College of Medicine , Burlington, VT, USA

[s ]Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University , Guangzhou, China

[t ]Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen , Essen, Germany

[u ]Department of Surgery, YLL School of Medicine, National University of Singapore , Singapore, Singapore

Author notes

CONTACT Bernd Giebel Bernd.Giebel@ 123456uk-essen.de Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen , Essen, Germany

Sai Kiang Lim saikiang.lim@ 123456imb.a-star.edu.sg Institute of Medical Biology, Agency for Science, Technology and Research , Singapore

[*]

Authors who are members of the Society for Clinical Research and Translation of Extracellular Vesicles Singapore (SOCRATES).

[‡]

Authors who are members of the International Society for Cell and Gene Therapy (ISCT)

[§]

Authors who are members of the International Society for Extracellular Vesicles (ISEV)

[¶]

Author who is member of the International Society of Blood Transfusion (ISBT)

Author information

Andrew F. Hill http://orcid.org/0000-0001-5581-2354

Article

Publisher ID: 1609206

DOI: 10.1080/20013078.2019.1609206

PMC ID: 6493293

PubMed ID: 31069028

SO-VID: e4a40abe-c690-4285-844f-3b32ca3d94a9

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 14 January 2019

Date revision received : 09 April 2019

Date accepted : 14 April 2019

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Tables: 1, References: 68, Pages: 13

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Defining mesenchymal stromal cell (MSC)-derived small extracellular vesicles for therapeutic applications

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ABSTRACT

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Most cited references 28

Mast cell- and dendritic cell-derived exosomes display a specific lipid composition and an unusual membrane organization.

Mesenchymal stem cell exosomes.

Molecular lipidomics of exosomes released by PC-3 prostate cancer cells.

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Cited by 281

Most referenced authors 1,982