Proangiogenic Compositions of Microvesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells

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.

Acute Hypoxic Stress Affects Migration Machinery of Tissue O2-Adapted Adipose Stromal Cells

“…In addition, we have demonstrated that hypoxic stress stimulates the secretion of proangiogenic factors (VEGF, IL-8) from tissue O 2 -adapted ASCs [45], which should promote angiogenesis. The above results correlate with the findings of other studies, confirming that hypoxic preconditioning promotes MSC angiogenic activity [41, 73]. Secondly, the release of chemoattractants from cells in the areas of damage creates a chemotactic gradient that stimulated MSC migration from perivascular niches towards the areas of injury, which are characterised by acute hypoxia.…”

Hypoxia-stimulated cardiac fibroblast production of IL-6 promotes myocardial fibrosis via the TGF-β1 signaling pathway

“…First, the most important effector for this is VEGF. 26 Second, Ang-1 regulates sprouting angiogenesis and vascular remodeling. 27 Third, VEGF, bFGF, and Ang-1 are specific mitogens of ECs in EC proliferation and migration.…”

Three decades of research on angiogenin: a review and perspective

“…The mast cell, a unique immune cell that accumulates in the stroma surrounding certain tumors, can also release ANG to induce neovascularization [129]. Moreover, MVs derived from mesenchymal stem cells under conditions of hypoxia or serum deprivation contain ANG, which mainly contributes to the angiogenesis-promoting functions of the MVs [130]. ANG can also induce vasculogenic mimicry of fibrosarcoma HT1080 cells [131].…”