Mesenchymal stem cells release exosomes that transfer miRNAs to endothelial cells and promote angiogenesis

Min Gong, Bin Yu, Jingcai Wang, Yigang Wang, Min Liu, Christian Paul, Ronald W. Millard, De Sheng Xiao, Muhammad Ashraf, Meifeng Xu

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

Mesenchymal stem cells (MSCs) have been found to benefit patients with a variety of ischemic diseases via promoting angiogenesis. It is also well established that exosomes secreted from MSCs deliver bioactive molecules, including microRNAs (miRs) to recipient cells. Therefore, we hypothesized that exosomes secreted from MSCs deliver miRs into endothelial cells and mediate angiogenesis. The pro-angiogenic stimulatory capacity of exosomes was investigated using tube-like structure formation and spheroid-based sprouting of human umbilical vein endothelial cells (HUVECs), and in vivo Matrigel plug assay. The secretion of pro-angiogenic miRs (pro-angiomiRs) from MSCs into culture medium and transfer of the miRs to HUVECs were confirmed using real-time quantitative PCR. Supplementation of the exosome secretion blocker GW4869 (10 μM) reduced the pro-angiomiRs in the MSC-derived conditioned medium (CdMMSC). Addition of exosomes isolated from CdMMSC could directly 1) promote HUVEC tube-like structure formation in vitro; 2) mobilize endothelial cells into Matrigel plug subcutaneously transplanted into mice; and 3) increase blood flow inside Matrigel plug. Fluorescence tracking showed that the exosomes were internalized rapidly by HUVECs causing an upregulated expression of pro-angiomiRs in HUVECs. Loss-andgain function of the pro-angiomiRs (e.g., miR-30b) in MSCs significantly altered the pro-angiogenic properties of these MSC-derived exosomes, which could be associated with the regulation of their targets in HUVECs. These results suggest that exosomal transfer of pro-angiogenic miRs plays an important role in MSC mediated angiogenesis and stem cell-to-endothelial cell communication.

Original languageEnglish (US)
Pages (from-to)45200-45212
Number of pages13
JournalOncotarget
Volume8
Issue number28
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

Keywords

  • Angiogenesis
  • Exosomes
  • Mesenchymal stem cells
  • miR-30b
  • miRNA transfer

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Gong, M., Yu, B., Wang, J., Wang, Y., Liu, M., Paul, C., Millard, R. W., Xiao, D. S., Ashraf, M., & Xu, M. (2017). Mesenchymal stem cells release exosomes that transfer miRNAs to endothelial cells and promote angiogenesis. Oncotarget, 8(28), 45200-45212. https://doi.org/10.18632/oncotarget.16778