Mesenchymal stem cells-derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis

Stella Cosenza; Karine Toupet; Marie Maumus; Patricia Luz-Crawford; Olivier Blanc-Brude; Christian Jorgensen; Danièle Noël

doi:10.7150/thno.21072

Mesenchymal stem cells-derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis

Stella Cosenza, Karine Toupet, Marie Maumus, Patricia Luz-Crawford, Olivier Blanc-Brude, Christian Jorgensen, Danièle Noël^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

371 Scopus citations

Abstract

Objectives: Mesenchymal stem cells (MSCs) release extracellular vesicles (EVs) that display a therapeutic effect in inflammatory disease models. Although MSCs can prevent arthritis, the role of MSCs-derived EVs has never been reported in rheumatoid arthritis. This prompted us to compare the function of exosomes (Exos) and microparticles (MPs) isolated from MSCs and investigate their immunomodulatory function in arthritis. Methods: MSCs-derived Exos and MPs were isolated by differential ultracentrifugation. Immunosuppressive effects of MPs or Exos were investigated on T and B lymphocytes in vitro and in the Delayed-Type Hypersensitivity (DTH) and Collagen-Induced Arthritis (CIA) models. Results: Exos and MPs from MSCs inhibited T lymphocyte proliferation in a dose-dependent manner and decreased the percentage of CD4⁺ and CD8⁺ T cell subsets. Interestingly, Exos increased Treg cell populations while parental MSCs did not. Conversely, plasmablast differentiation was reduced to a similar extent by MSCs, Exos or MPs. IFN-γ priming of MSCs before vesicles isolation did not influence the immunomodulatory function of isolated Exos or MPs. In DTH, we observed a dose-dependent anti-inflammatory effect of MPs and Exos, while in the CIA model, Exos efficiently decreased clinical signs of inflammation. The beneficial effect of Exos was associated with fewer plasmablasts and more Breg-like cells in lymph nodes. Conclusions: Both MSCs-derived MPs and Exos exerted an anti-inflammatory role on T and B lymphocytes independently of MSCs priming. However, Exos were more efficient in suppressing inflammation in vivo. Our work is the first demonstration of the therapeutic potential of MSCs-derived EVs in inflammatory arthritis.

Original language	English
Pages (from-to)	1399-1410
Number of pages	12
Journal	Theranostics
Volume	8
Issue number	5
DOIs	https://doi.org/10.7150/thno.21072
State	Published - 2018

Bibliographical note

Funding Information:
Work in the laboratory Inserm U1183 was supported by the Inserm Institute and the University of Montpellier. This project has received funding from the European Union’s Horizon 2020 Programme (project ADIPOA2, grant agreement no: 643809). The materials presented and views expressed here are the responsibility of the authors only. The EU Commission takes no responsibility for any use made of the information set out. Study was also supported by the Fondation de l’Avenir, Paris, France (AP-RMA-2015-013). We thank the Agence Nationale pour la Recherche for support of the national infrastructure: "ECELLFRANCE: Development of a national adult mesenchymal stem cell based therapy platform" (ANR-11-INSB-005).

Publisher Copyright:
© Ivyspring International Publisher.

Keywords

Cell therapy
Extracellular vesicles
Mesenchymal stem cells
Rheumatoid arthritis
Trophic factors

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10.7150/thno.21072

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title = "Mesenchymal stem cells-derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis",

abstract = "Objectives: Mesenchymal stem cells (MSCs) release extracellular vesicles (EVs) that display a therapeutic effect in inflammatory disease models. Although MSCs can prevent arthritis, the role of MSCs-derived EVs has never been reported in rheumatoid arthritis. This prompted us to compare the function of exosomes (Exos) and microparticles (MPs) isolated from MSCs and investigate their immunomodulatory function in arthritis. Methods: MSCs-derived Exos and MPs were isolated by differential ultracentrifugation. Immunosuppressive effects of MPs or Exos were investigated on T and B lymphocytes in vitro and in the Delayed-Type Hypersensitivity (DTH) and Collagen-Induced Arthritis (CIA) models. Results: Exos and MPs from MSCs inhibited T lymphocyte proliferation in a dose-dependent manner and decreased the percentage of CD4+ and CD8+ T cell subsets. Interestingly, Exos increased Treg cell populations while parental MSCs did not. Conversely, plasmablast differentiation was reduced to a similar extent by MSCs, Exos or MPs. IFN-γ priming of MSCs before vesicles isolation did not influence the immunomodulatory function of isolated Exos or MPs. In DTH, we observed a dose-dependent anti-inflammatory effect of MPs and Exos, while in the CIA model, Exos efficiently decreased clinical signs of inflammation. The beneficial effect of Exos was associated with fewer plasmablasts and more Breg-like cells in lymph nodes. Conclusions: Both MSCs-derived MPs and Exos exerted an anti-inflammatory role on T and B lymphocytes independently of MSCs priming. However, Exos were more efficient in suppressing inflammation in vivo. Our work is the first demonstration of the therapeutic potential of MSCs-derived EVs in inflammatory arthritis.",

keywords = "Cell therapy, Extracellular vesicles, Mesenchymal stem cells, Rheumatoid arthritis, Trophic factors",

author = "Stella Cosenza and Karine Toupet and Marie Maumus and Patricia Luz-Crawford and Olivier Blanc-Brude and Christian Jorgensen and Dani{\`e}le No{\"e}l",

note = "Funding Information: Work in the laboratory Inserm U1183 was supported by the Inserm Institute and the University of Montpellier. This project has received funding from the European Union{\textquoteright}s Horizon 2020 Programme (project ADIPOA2, grant agreement no: 643809). The materials presented and views expressed here are the responsibility of the authors only. The EU Commission takes no responsibility for any use made of the information set out. Study was also supported by the Fondation de l{\textquoteright}Avenir, Paris, France (AP-RMA-2015-013). We thank the Agence Nationale pour la Recherche for support of the national infrastructure: {"}ECELLFRANCE: Development of a national adult mesenchymal stem cell based therapy platform{"} (ANR-11-INSB-005). Publisher Copyright: {\textcopyright} Ivyspring International Publisher.",

year = "2018",

doi = "10.7150/thno.21072",

language = "English",

volume = "8",

pages = "1399--1410",

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T1 - Mesenchymal stem cells-derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis

AU - Cosenza, Stella

AU - Toupet, Karine

AU - Maumus, Marie

AU - Luz-Crawford, Patricia

AU - Blanc-Brude, Olivier

AU - Jorgensen, Christian

AU - Noël, Danièle

N1 - Funding Information: Work in the laboratory Inserm U1183 was supported by the Inserm Institute and the University of Montpellier. This project has received funding from the European Union’s Horizon 2020 Programme (project ADIPOA2, grant agreement no: 643809). The materials presented and views expressed here are the responsibility of the authors only. The EU Commission takes no responsibility for any use made of the information set out. Study was also supported by the Fondation de l’Avenir, Paris, France (AP-RMA-2015-013). We thank the Agence Nationale pour la Recherche for support of the national infrastructure: "ECELLFRANCE: Development of a national adult mesenchymal stem cell based therapy platform" (ANR-11-INSB-005). Publisher Copyright: © Ivyspring International Publisher.

PY - 2018

Y1 - 2018

N2 - Objectives: Mesenchymal stem cells (MSCs) release extracellular vesicles (EVs) that display a therapeutic effect in inflammatory disease models. Although MSCs can prevent arthritis, the role of MSCs-derived EVs has never been reported in rheumatoid arthritis. This prompted us to compare the function of exosomes (Exos) and microparticles (MPs) isolated from MSCs and investigate their immunomodulatory function in arthritis. Methods: MSCs-derived Exos and MPs were isolated by differential ultracentrifugation. Immunosuppressive effects of MPs or Exos were investigated on T and B lymphocytes in vitro and in the Delayed-Type Hypersensitivity (DTH) and Collagen-Induced Arthritis (CIA) models. Results: Exos and MPs from MSCs inhibited T lymphocyte proliferation in a dose-dependent manner and decreased the percentage of CD4+ and CD8+ T cell subsets. Interestingly, Exos increased Treg cell populations while parental MSCs did not. Conversely, plasmablast differentiation was reduced to a similar extent by MSCs, Exos or MPs. IFN-γ priming of MSCs before vesicles isolation did not influence the immunomodulatory function of isolated Exos or MPs. In DTH, we observed a dose-dependent anti-inflammatory effect of MPs and Exos, while in the CIA model, Exos efficiently decreased clinical signs of inflammation. The beneficial effect of Exos was associated with fewer plasmablasts and more Breg-like cells in lymph nodes. Conclusions: Both MSCs-derived MPs and Exos exerted an anti-inflammatory role on T and B lymphocytes independently of MSCs priming. However, Exos were more efficient in suppressing inflammation in vivo. Our work is the first demonstration of the therapeutic potential of MSCs-derived EVs in inflammatory arthritis.

AB - Objectives: Mesenchymal stem cells (MSCs) release extracellular vesicles (EVs) that display a therapeutic effect in inflammatory disease models. Although MSCs can prevent arthritis, the role of MSCs-derived EVs has never been reported in rheumatoid arthritis. This prompted us to compare the function of exosomes (Exos) and microparticles (MPs) isolated from MSCs and investigate their immunomodulatory function in arthritis. Methods: MSCs-derived Exos and MPs were isolated by differential ultracentrifugation. Immunosuppressive effects of MPs or Exos were investigated on T and B lymphocytes in vitro and in the Delayed-Type Hypersensitivity (DTH) and Collagen-Induced Arthritis (CIA) models. Results: Exos and MPs from MSCs inhibited T lymphocyte proliferation in a dose-dependent manner and decreased the percentage of CD4+ and CD8+ T cell subsets. Interestingly, Exos increased Treg cell populations while parental MSCs did not. Conversely, plasmablast differentiation was reduced to a similar extent by MSCs, Exos or MPs. IFN-γ priming of MSCs before vesicles isolation did not influence the immunomodulatory function of isolated Exos or MPs. In DTH, we observed a dose-dependent anti-inflammatory effect of MPs and Exos, while in the CIA model, Exos efficiently decreased clinical signs of inflammation. The beneficial effect of Exos was associated with fewer plasmablasts and more Breg-like cells in lymph nodes. Conclusions: Both MSCs-derived MPs and Exos exerted an anti-inflammatory role on T and B lymphocytes independently of MSCs priming. However, Exos were more efficient in suppressing inflammation in vivo. Our work is the first demonstration of the therapeutic potential of MSCs-derived EVs in inflammatory arthritis.

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KW - Trophic factors

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Mesenchymal stem cells-derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis

Abstract

Bibliographical note

Keywords

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