Abstract
Introduction & ObjectiveMicrovesicles (MVs) derived from mesenchymal stem cells (MSCs) have been shown to promote angiogenesis. This study was aimed to shed a light on the mechanisms by analyzing the angiogenesis-promoting compositions of MSC-MVs. Also we try to figure out the impact of hypoxia on angiogenesis.MethodsMVs were isolated from the culture supernatants of MSCs under hypoxia/normoxia and serum-deprivation condition. The morphological features of MVs were revealed by an electron microscope and the origin of the MVs was identified by a bead-bound assay. An antibody array was used to analyze the expression of angiogenic cytokines from MVs and the parent MSCs as well. The major candidate factors were screened and the results were validated by immune blotting.ResultsMSC-MVs were around 80 nm in diameter. They expressed CD29, CD44, and CD73, but not CD31 and CD45. Antibody array showed that both MSCs and MVs expressed many angiogenesis-promoting biomolecules, including interleukin-6 (IL-6), basic fibroblast growth factors (bFGF), and recptor of urokinase-type plasminogen activator (UPAR). MSC-MVs contained angiogenin, vascular endothelial growth factor (VEGF), monocyte chemotactic protein-1 (MCP-1) and the receptor-2 for vascular endothelial growth factor at higher levels than the parent MSCs. Under hypoxic condition most cytokines were expressed in greater quantity than normoxic in MSCs while in MVs there was no significant difference between hypoxic and normoxic conditions except UPAR, Angiogenin, VEGF, IGF, Tie-2/TEK, and IL-6 which were higher in MVs under hypoxic conditions than those in normoxic condition.ConclusionUpon serum-deprivation condition, MSCs could secrete MVs that contain a variety of factors contributing to their angiogenesis-promoting function. And among them, Angiogenin, VEGF, MCP-1, VEGF R2 might be of greater importance than the other cytokines. Also UPAR, Angiogenin, VEGF, IGF, Tie-2/TEK, IL-6 might be responsible for hypoxia-augmented proangiogenic effects of MVs.
Highlights
Introduction & ObjectiveMicrovesicles (MVs) derived from mesenchymal stem cells (MSCs) have been shown to promote angiogenesis
The majority of cells showed a prominent presence of the MSC surface markers CD73, CD44, CD106 as well as PDGFRb
The results showed that uPAR, Metalloproteinase inhibitor 2 (TIMP2), growth-related oncogene (GRO), Metalloproteinase inhibitor 1 (TIMP-1), Insulin like growth factor I (IGF-I), Basic fibroblast growth factors, interleukin-6 (IL-6), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), Hepatocyte growth factor (HGF), Transforming growth factor b1 (TGFb1), monocyte chemotactic protein-1 (MCP-1), MMP-1, Tie-2/TEK, ENA-78, IL-1a, Follistatin, Angiogenin, IL-1b, VEGF R2, MCP-3, MCP-2, GM
Summary
Microvesicles (MVs) derived from mesenchymal stem cells (MSCs) have been shown to promote angiogenesis. MVs are mobile and small vesicles (100–1000 mm) surrounded by the phospholipid bilayer and released by direct budding and blebbing of the plasma membrane They frequently expose at their surface phosphatidylserine (PS) and express antigenic profile characteristic of the cell they originate. In a rat hind-limb ischemia model, MSC-MVs were shown to significantly improve the blood flow recovery [7] Those results indicate that MVs releasing may be one of the major mechanisms underlying the effectiveness of MSCs therapy by promoting angiogenesis both in vitro and in vivo. In this article by comparing the level of angiogenic cytokines in MVs and their parent MSCs, we try to figure out the major candidate factors promoting angiogenesis. By comparing the expression of angiogenesis cytokines under hypoxia and normoxia, we try to figure out the impact of hypoxia on angiogenesis
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