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Boosting Angiogenesis with Microvesicles and miRNA

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Review of “Adipose-Derived Stem Cells Induce Angiogenesis via Microvesicle Transport of miRNA-31” from Stem Cells Translational Medicine by Stuart P. Atkinson

Adipose-derived mesenchymal stem cells (ASCs) have the potential to promote angiogenesis in ischemic tissues via the secretion of a wide-range of protein factors [1-3]. In addition, cell-released microvesicles (MVs)/exosomes may also be important, although the cargos which these plasma membrane-derived vesicles contain still remain to be studied in-depth [4].

To address this problem, researchers from the laboratory of Dong Liu (Morehouse School of Medicine, Atlanta, Georgia, USA) assessed ASC-derived MVs, finding that they have potent angiogenic properties due to the enrichment of an miRNA which targets an anti-angiogenesis gene [5]. This exciting new study not only describes new mechanisms to enhance angiogenesis but may also allow the construction of novel cell-free therapies.

Initial experimentation demonstrated that ASC-derived MVs induced migration and tube formation of human umbilical vein endothelial cells (HUVECs). However, MVs collected from ASCs conditioned with endothelial differentiation medium (EDM) increased endothelial cell migration and tube formation to a higher level (See figure, MV = ASC microvesicles, MV-P = microvesicles from pre-conditioned ASCs).

To discover what caused this pro-angiogenic effect, the authors of the study assessed isolated MVs, finding the specific enrichment of various miRNAs. Array analysis established that the upregulated miR-31 miRNA represented the only known proangiogenic miRNA of the top 15 most abundant MV-derived miRNAs and also that EDM-preconditioning of ASCs elevated the levels of MV miR-31. The study confirmed the pro-angiogenic properties of miR-31 using migration and tube formation assays in vitro, using an aortic ring microvessel outgrowth assay ex vivo, and using a mouse Matrigel plug vascular formation assay in vivo.

But how is this single miRNA species inducing angiogenesis in such a significant manner? Analysis of factors downregulated in endothelial cells in response to EDM-conditioned ASC-CM found that only FIH1 (factor-inhibiting HIF-1), a known anti-angiogenic gene, represented a known target of miR-31. Encouragingly, treatment of endothelial cells with a miR-31 precursor reduced FIH1 mRNA and protein levels, so suggesting that FIH1 may represent a bona fide target for both miR-31 and new pro-angiogenic therapies.

A better understanding of microvesicular contents and function may, in the future, lead to the construction of novel, cell-free therapies for a number of diseases and disorders. This study underlines the importance of the miR-31-FIH1 axis in the promotion of angiogenesis by endothelial-induced ASC-MVs and, in doing so, may provide us with a means to enhance angiogenic therapy for ischemic diseases. However, this study also highlights that cell-based therapies may also be improved via specific pre-conditioning strategies, such as hypoxia or differentiation-specific media compositions.

References

  1. Miranville A, Heeschen C, Sengenes C, et al. Improvement of postnatal neovascularization by human adipose tissue-derived stem cells. Circulation 2004;110:349-355.
  2. Nakagami H, Maeda K, Morishita R, et al. Novel autologous cell therapy in ischemic limb disease through growth factor secretion by cultured adipose tissue-derived stromal cells. Arterioscler Thromb Vasc Biol 2005;25:2542-2547.
  3. Valina C, Pinkernell K, Song YH, et al. Intracoronary administration of autologous adipose tissue-derived stem cells improves left ventricular function, perfusion, and remodelling after acute myocardial infarction. Eur Heart J 2007;28:2667-2677.
  4. Camussi G, Deregibus MC, Bruno S, et al. Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney Int 2010;78:838-848.
  5. Kang T, Jones TM, Naddell C, et al. Adipose-Derived Stem Cells Induce Angiogenesis via Microvesicle Transport of miRNA-31. Stem Cells Translational Medicine 2016;5:440-450.