OC 18.1 - Therapeutic potential of CD146 extracellular vesicles for the treatment of atherosclerosis

Sunday, July 10, 2022

10:45 AM – 11:00 AM

Location: ExCel Center, ICC Capital Suite Room 2-4

Presentation Format: Virtual

Co-Author(s)

CD

Cléa Dubrou

PhD student
INSERM/Aix-Marseille University
Marseille, Provence-Alpes-Cote d'Azur, France
MB

Muriel Blin

PhD
INSERM/Aix-Marseille University
Marseille, Provence-Alpes-Cote d'Azur, France
KF

Karim Fallague

Tech
INSERM/Aix-Marseille University
Marseille, Provence-Alpes-Cote d'Azur, France
RB

Richard Bachelier

Research scientist
Aix-Marseille Univ, INSERM, INRAE, C2VN, Marseille, France
Marseille, Provence-Alpes-Cote d'Azur, France
CC

Corinne Chareyre

Tech
INSERM/Aix-Marseille University
Marseille, Provence-Alpes-Cote d'Azur, France
SR

Stephane Robert

Engeneer
Aix Marseille University, INSERM 1263, INRAE, C2VN, Marseille, France
Marseille, Provence-Alpes-Cote d'Azur, France
RL

Romaric Lacroix, PharmD PhD

PharmD. PhD. - Professor of Immunology and Hematology
Aix-Marseille Univ, APHM, INSERM, INRAE, C2VN, Laboratory of Hematology and Vascular Biology, University Hospital La Conception, Marseille, France
Marseille, Provence-Alpes-Cote d'Azur, France
Françoise Dignat-George

Professor, Director at C2VN
Aix-Marseille University
Marseille, Provence-Alpes-Cote d'Azur, France
NB

Nathalie Bardin

Professor
Aix-Marseille Univ, APHM, INSERM, INRAE, C2VN -Laboratory of Hematology and Vascular Biology, University Hospital La Conception, Marseille, France.
Marseille, Provence-Alpes-Cote d'Azur, France
MB

Marcel Blot-Chabaud

Research director
INSERM/Aix-Marseille University
Marseille, Provence-Alpes-Cote d'Azur, France

Presenting Author(s)

Aurélie leroyer, PhD

Assistant professor
INSERM/Aix-Marseille University
Marseille, Provence-Alpes-Cote d'Azur, France

Background: Atherosclerosis remains the biggest cause of death worldwide despite the wide use of LDL-lowering therapy, thus targeting inflammation during its pathogenesis appears to be an alternative to the actual therapies. We previously showed that the expression of the adhesion molecule CD146 on foamy macrophages allows to reduce CCL5 and subsequent inflammation within the atherosclerotic plaque.

Aims: As extracellular vesicles may serve as potential clinical delivery devices through specific interactions with target cells, we propose to delay the progression of atherosclerosis by delivering athero-protective CD146 using extracellular vesicles in order to overexpress it within atheroma.

Methods: For this, we generated and purified extracellular vesicles from mouse endothelial cells which strongly express CD146 and from mouse endothelial cells deleted in CD146 as a control.

Results: Mouse bone-marrow-derived macrophages were stimulated with CD146 extracellular vesicles previously labeled with CMFDA and we demonstrated that vesicles were rapidly incorporated by macrophages within 15 minutes. In vivo, CD146 extracellular vesicles were able to reach the inflammatory atherosclerotic sites in both heart and aorta within 30 minutes after their injection. Macrophages in culture were further stimulated with extracellular vesicles and both qPCR, flow cytometry and ELISA analysis showed that CD146 extracellular vesicles induce macrophage polarization towards an anti-inflammatory phenotype by decreasing TNF-α, IL-6, CCL-5 and increasing IL-10, TGF-β. Then, ApoE -/- mice were intraveneously injected with extracellular vesicles once every 15 days during 6 weeks. We demonstrated that the delivery of CD146 using extracellular vesicles to ApoE -/- mice significantly delayed atherosclerosis (decrease of 53% plaque area), decreased plaque inflammation (decrease of 46% of neutrophils content and 87% of CCL5 content), and promoted the increase of CD206 expression, hallmark of anti-inflammatory “M2” macrophages whereas the expression of CD16/32 “M1” marker was decreased.

Conclusion(s): Altogether, our study has demonstrated proof-of-concept that delivering CD146 using extracellular vesicles delays inflammation and atherosclerosis.