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Extracellular Vesicles Derived from Adipose Mesenchymal Stem Cells Regulate the Phenotype of Smooth Muscle Cells to Limit Intimal Hyperplasia

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Abstract

Purpose

Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) play important roles in the reduction of inflammation in multiple disease models. However, their role in vein graft (VG) remodeling is undefined. We aimed to investigate the effect of EVs from adipose MSCs (ADMSC-EVs) on VG intimal hyperplasia and to explore the possible mechanisms.

Methods

After generation and characterization of control-EVs and ADMSC-EVs in vitro, we investigated their effect on the proliferation and migration of vascular smooth muscle cells (VSMCs) in vitro. Next, we established a mouse model of VG transplantation. Mice underwent surgery and received control-EVs or ADMSC-EVs by intraperitoneal injection every other day for 20 days. VG remodeling was evaluated after 4 weeks. We also assessed the effect of ADMSC-EVs on macrophage migration and inflammatory cytokine expression.

Results

Significant inhibitory effects of ADMSC-EVs on in vitro VSMC proliferation (p < 0.05) and migration (p < 0.05) were observed compared with control-EVs. The extent of intimal hyperplasia was significantly decreased in ADMSC-EV-treated mice compared with control-EV-treated mice (26 ± 8.4 vs. 45 ± 9.0 μm, p < 0.05). A reduced presence of macrophages was observed in ADMSC-EV-treated mice (p < 0.05). Significantly decreased expression of inflammatory cytokines interleukin (IL)-6 and monocyte chemoattractant protein-1 (MCP-1) was also found in the ADMSC-EV-treated group (both p < 0.05). In addition, phosphorylation of Akt, Erk1/2, and p38 in VGs was decreased in the ADMSC-EV-treated group.

Conclusions

We demonstrated that ADMSC-EVs exert an inhibitory effect on VG neointima formation by regulating VSMC proliferation and migration, macrophage migration, inflammatory cytokine expression, and the related signaling pathways.

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    Authors and Affiliations

    1. Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 600 Yishan Rd, Shanghai, 200233, China

      Rong Liu, Hong Shen, Jian Ma, Leiqing Sun & Meng Wei

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    1. Rong Liu
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    2. Hong Shen
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    3. Jian Ma
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    4. Leiqing Sun
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    5. Meng Wei
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    Correspondence to Meng Wei.

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    The authors declare no conflicts of interest.

    Funding Support

    This work was supported by the Natural Science Foundation of the Shanghai Municipal Government (13AR1459200).

    Additional information

    Rong Liu and Hong Shen contributed equally to this work.

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    Figure S1

    EMPs are taken up by murine vessel. A, PKH26-labeled MVs (20 μg in 150 μL M-199 medium) or vehicle was injected intraperitoneally into C57BL/6 mice. After 30 min, the animals were euthanized. En face staining of aortic endothelium showed the internalization of MVs (red) into the murine vessel. Nuclei were stained with DAPI (blue). Magnification, ×200. B, Murine carotid arteries were isolated and perfused with PKH26-labeled EMPs for 30 min. After washing, PKH26-labeled EMPs (red spots) were detectable in cross-sections from EMP-perfused carotid arteries. Perfusion with M-199 served as control. Bar in cross-section pictures, 100 μm. Bar in cutouts, 50 μm. (GIF 23 kb)

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    Liu, R., Shen, H., Ma, J. et al. Extracellular Vesicles Derived from Adipose Mesenchymal Stem Cells Regulate the Phenotype of Smooth Muscle Cells to Limit Intimal Hyperplasia. Cardiovasc Drugs Ther 30, 111–118 (2016). https://doi.org/10.1007/s10557-015-6630-5

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    • DOI: https://doi.org/10.1007/s10557-015-6630-5

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