Alternative therapeutic strategy for existing aortic aneurysms using mesenchymal stem cell–derived exosomes

ABSTRACT

Background

Several studies demonstrated the therapeutic potential of mesenchymal stem cell–derived exosomes (MSC-exs) based on their anti-inflammatory properties. The objective was to determine the therapeutic effects of MSC-exs on aortic aneurysms (AAs) caused by atherosclerosis.

Research design and methods

Apolipoprotein E knockout mice with AAs induced by angiotensin II were injected with MSC-exs or saline as a control. The change in the diameter of the aorta was measured. The expression of AA-related proteins and the histology of the aortic wall were investigated at 1 week after treatment. MicroRNA and protein profiles of MSC-exs were examined.

Results

MSC-exs significantly attenuated AA progression (2.04 ± 0.20 mm in the saline group and 1.34 ± 0.13 mm in the MSC-ex group, P = 0.004). In the MSC-ex group, the expression of IL-1β, TNF-α and MCP-1 decreased, and expression of IGF-1 and TIMP-2 increased. MSC-ex induced the M2 phenotype in macrophages and suppressed the destruction of the elastic lamellae in the aortic wall. MSC-exs contained high levels of 10 microRNAs that inhibit AA formation and 13 proteins that inhibit inflammation and promote extracellular matrix synthesis.

Conclusions

MSC-ex might be a novel alternative therapeutic tool for treatment of existing AAs.

KEYWORDS:

• Aortic aneurysm
• exosome
• extracellular vesicles
• mesenchymal stem cells
• microRNA
• stem cell therapy

Abbreviations

AA = aortic aneurysm; αSMA = alpha smooth muscle actin; ANOVA = analysis of variance; apoE = apolipoprotein E; ATII = angiotensin II; BM-MSC = bone marrow-derived mesenchymal stem cell; CD = cluster of differentiation; DAPI = 4′,6-diamidino-2-phenylindole dihydrochloride; DMEM = Dulbecco’s Modified Eagle’s Medium; ECM = extracellular matrix; ELISA = enzyme-linked immunosorbent assay; EvG = Elastica van Gieson; EV = extracellular vesicle; FBS = fetal bovine serum; FITC = fluorescein isothiocyanate; GAPDH = glyceraldehyde 3-phosphate dehydrogenase; IGF = insulin-like growth factor; IGFBP = insulin-like growth factor binding protein; IL = interleukin; iv = intravenous; Lox = lysyl oxidase; MCP = monocyte chemotactic protein; miR = microRNA; MISEV = Minimal Information for Studies of Extracellular Vesicles; MMP = matrix metalloproteinase; MSC = mesenchymal stem cell; MSC-ex = MSC-derived exosome; NF = nuclear factor; PE = phycoerythrin; PBS = phosphate-buffered saline; qRT-PCR = quantitative reserve transcription-polymerase chain reaction; SLPI = secretory leukocyte proteinase inhibitor; SMC = smooth muscle cell; TEM = transmission electron microscopy; TIMP = tissue inhibitor of metalloproteinase; TGF = transforming growth factor; TNF = tumor necrosis factor.

Title: Alternative therapeutic strategy for existing aortic aneurysms using mesenchymal stem cell–derived exosomes

Acknowledgments

The authors wish to acknowledge the Division of Experimental Animals, Nagoya University, and the Division for Medical Research Engineering, Nagoya University Graduate School of Medicine, for allowing the use of their equipment, including a FACSCalibur and a Leica Microsystems microtome cryostat.

Declaration of interests

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Author contributions

M.K. designed and performed the in vitro and in vivo experiments, analyzed the data, and wrote the manuscript; Y.N. and A.Y.O. contributed to the conceptual design, performed the in vitro and in vivo experiments, analyzed the data, and reviewed the manuscript; K.L.F., M.M., Y.T., and A.U. contributed to the conceptual design and reviewed the manuscript. All authors drafted and/or critically revised the manuscript and approved the final draft for submission.

Additional information

Funding

This study was supported in part by a grant from the Japan Society for the Promotion of Science (KAKENHI grant number JP26893110).