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

48 Citations (Scopus)

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

Fingerprint

Exosomes
MicroRNAs
Mesenchymal Stromal Cells
Human Umbilical Vein Endothelial Cells
Endothelial Cells
Conditioned Culture Medium
Cell Communication
Culture Media
Real-Time Polymerase Chain Reaction
Stem Cells
Cell Culture Techniques
Fluorescence

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

Mesenchymal stem cells release exosomes that transfer miRNAs to endothelial cells and promote angiogenesis. / Gong, Min; Yu, Bin; Wang, Jingcai; Wang, Yigang; Liu, Min; Paul, Christian; Millard, Ronald W.; Xiao, De Sheng; Ashraf, Muhammad; Xu, Meifeng.

In: Oncotarget, Vol. 8, No. 28, 01.01.2017, p. 45200-45212.

Research output: Contribution to journalArticle

Gong, M, Yu, B, Wang, J, Wang, Y, Liu, M, Paul, C, Millard, RW, Xiao, DS, Ashraf, M & Xu, M 2017, 'Mesenchymal stem cells release exosomes that transfer miRNAs to endothelial cells and promote angiogenesis', Oncotarget, vol. 8, no. 28, pp. 45200-45212. https://doi.org/10.18632/oncotarget.16778
Gong, Min ; Yu, Bin ; Wang, Jingcai ; Wang, Yigang ; Liu, Min ; Paul, Christian ; Millard, Ronald W. ; Xiao, De Sheng ; Ashraf, Muhammad ; Xu, Meifeng. / Mesenchymal stem cells release exosomes that transfer miRNAs to endothelial cells and promote angiogenesis. In: Oncotarget. 2017 ; Vol. 8, No. 28. pp. 45200-45212.
@article{70d45324f5f8473d96317af4c936e2e3,
title = "Mesenchymal stem cells release exosomes that transfer miRNAs to endothelial cells and promote angiogenesis",
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.",
keywords = "Angiogenesis, Exosomes, Mesenchymal stem cells, miR-30b, miRNA transfer",
author = "Min Gong and Bin Yu and Jingcai Wang and Yigang Wang and Min Liu and Christian Paul and Millard, {Ronald W.} and Xiao, {De Sheng} and Muhammad Ashraf and Meifeng Xu",
year = "2017",
month = "1",
day = "1",
doi = "10.18632/oncotarget.16778",
language = "English (US)",
volume = "8",
pages = "45200--45212",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "28",

}

TY - JOUR

T1 - Mesenchymal stem cells release exosomes that transfer miRNAs to endothelial cells and promote angiogenesis

AU - Gong, Min

AU - Yu, Bin

AU - Wang, Jingcai

AU - Wang, Yigang

AU - Liu, Min

AU - Paul, Christian

AU - Millard, Ronald W.

AU - Xiao, De Sheng

AU - Ashraf, Muhammad

AU - Xu, Meifeng

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

KW - Angiogenesis

KW - Exosomes

KW - Mesenchymal stem cells

KW - miR-30b

KW - miRNA transfer

UR - http://www.scopus.com/inward/record.url?scp=85022226203&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85022226203&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.16778

DO - 10.18632/oncotarget.16778

M3 - Article

VL - 8

SP - 45200

EP - 45212

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 28

ER -