Role of MicroRNAs 99b, 181a, and 181b in the differentiation of human embryonic stem cells to vascular endothelial cells

Kane, N. M. et al. (2012) Role of MicroRNAs 99b, 181a, and 181b in the differentiation of human embryonic stem cells to vascular endothelial cells. Stem Cells, 30(4), pp. 643-654. (doi: 10.1002/stem.1026)

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MicroRNAs (miRNAs) are short noncoding RNAs, which post-transcriptionally regulate gene expression. miRNAs are transcribed as precursors and matured to active forms by a series of enzymes, including Dicer. miRNAs are important in governing cell differentiation, development, and disease. We have recently developed a feeder- and serum-free protocol for direct derivation of endothelial cells (ECs) from human embryonic stem cells (hESCs) and provided evidence of increases in angiogenesis-associated miRNAs (miR-126 and -210) during the process. However, the functional role of miRNAs in hESC differentiation to vascular EC remains to be fully interrogated. Here, we show that the reduction of miRNA maturation induced by Dicer knockdown suppressed hES-EC differentiation. A miRNA microarray was performed to quantify hES-EC miRNA profiles during defined stages of endothelial differentiation. miR-99b, -181a, and -181b were identified as increasing in a time- and differentiation-dependent manner to peak in mature hESC-ECs and adult ECs. Augmentation of miR-99b, -181a, and -181b levels by lentiviral-mediated transfer potentiated the mRNA and protein expression of EC-specific markers, Pecam1 and VE Cadherin, increased nitric oxide production, and improved hES-EC-induced therapeutic neovascularization in vivo. Conversely, knockdown did not impact endothelial differentiation. Our results suggest that miR-99b, -181a, and -181b comprise a component of an endothelial-miRNA signature and are capable of potentiating EC differentiation from pluripotent hESCs.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Baker, Professor Andrew and Kane, Dr Nicole and Mountford, Dr Joanne and McCahill, Dr Angela and Howard, Miss Lynsey and Lu, Dr Ruifang and Milligan, Professor Graeme and Delles, Professor Christian and MacKenzie, Dr Ruth and Meloni, Dr Marco and McClure, Dr John
Authors: Kane, N. M., Howard, L., Descamps, B., Meloni, M., McClure, J., Lu, R., McCahill, A., Breen, C., MacKenzie, R. M., Delles, C., Mountford, J. C., Milligan, G., Emanueli, C., and Baker, A. H.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:Stem Cells
Publisher:AlphaMed Press, Inc.
ISSN (Online):1549-4918
Published Online:22 March 2012
Copyright Holders:Copyright © 2012 The Authors
First Published:First published in Stem Cells 30(4):643-654
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
478611Interrogation and manipulation of micro RNA during differentiation of human ES cells to cardiomyocyte and vascular lineagesAndrew BakerBritish Heart Foundation (BHF)PG/08/107/26160Institute of Cardiovascular and Medical Sciences