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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 ?M) 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-and-gain 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.

SUBMITTER: Gong M

PROVIDER: S-EPMC5542178 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

Gong Min M Yu Bin B Wang Jingcai J Wang Yigang Y Liu Min M Paul Christian C Millard Ronald W RW Xiao De-Sheng DS Ashraf Muhammad M Xu Meifeng M

Oncotarget 20170701 28

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 sp ...[more]

PMID: 28423355

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Project description:BackgroundThe therapeutic potential of mesenchymal stem cells (MSCs) may be attributed partly to humoral factors such as growth factors, cytokines, and chemokines. Human term placental tissue-derived MSCs (PlaMSCs), or conditioned medium left over from cultures of these cells, have been reported to enhance angiogenesis. Recently, the exosome, which can transport a diverse suite of macromolecules, has gained attention as a novel intercellular communication tool. However, the potential role of the exosome in PlaMSC therapeutic action is not well understood. The purpose of this study was to evaluate PlaMSC-derived exosome angiogenesis promotion in vitro and in vivo.MethodsMSCs were isolated from human term placental tissue by enzymatic digestion. Conditioned medium was collected after 48-h incubation in serum-free medium (PlaMSC-CM). Angiogenic factors present in PlaMSC-CM were screened by a growth factor array. Exosomes were prepared by ultracentrifugation of PlaMSC-CM, and confirmed by transmission electron microscopy, dynamic light scattering, and western blot analyses. The proangiogenic activity of PlaMSC-derived exosomes (PlaMSC-exo) was assessed using an endothelial tube formation assay, a cell migration assay, and reverse transcription-PCR analysis. The in-vivo angiogenic activity of PlaMSC-exo was evaluated using a murine auricle ischemic injury model.ResultsPlaMSC-CM contained both angiogenic and angiostatic factors, which enhanced endothelial tube formation. PlaMSC-exo were incorporated into endothelial cells; these exosomes stimulated both endothelial tube formation and migration, and enhanced angiogenesis-related gene expression. Laser Doppler blood flow analysis showed that PlaMSC-exo infusion also enhanced angiogenesis in an in-vivo murine auricle ischemic injury model.ConclusionsPlaMSC-exo enhanced angiogenesis in vitro and in vivo, suggesting that exosomes play a role in the proangiogenic activity of PlaMSCs. PlaMSC-exo may be a novel therapeutic approach for treating ischemic diseases.

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

Publications

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

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