BDNF (Brain-Derived Neurotrophic Factor) Promotes Embryonic Stem Cells Differentiation to Endothelial Cells Via a Molecular Pathway, Including MicroRNA-214, EZH2 (Enhancer of Zeste Homolog 2), and eNOS (Endothelial Nitric Oxide Synthase)

Abstract

Objective- The NTs (neurotrophins), BDNF (brain-derived neurotrophic factor) and NT-3 promote vascular development and angiogenesis. This study investigated the contribution of endogenous NTs in embryonic stem cell (ESC) vascular differentiation and the potential of exogenous BDNF to improve the process of ESC differentiation to endothelial cells (ECs). Approach and Results- Mouse ESCs were differentiated into vascular cells using a 2-dimensional embryoid body (EB) model. Supplementation of either BDNF or NT-3 increased EC progenitors' abundance at day 7 and enlarged the peripheral vascular plexus with ECs and SM22α+ (smooth muscle 22 alpha-positive) smooth muscle cells by day 13. Conversely, inhibition of either BDNF or NT-3 receptor signaling reduced ECs, without affecting smooth muscle cells spread. This suggests that during vascular development, endogenous NTs are especially relevant for endothelial differentiation. At mechanistic level, we have identified that BDNF-driven ESC-endothelial differentiation is mediated by a pathway encompassing the transcriptional repressor EZH2 (enhancer of zeste homolog 2), microRNA-214 (miR-214), and eNOS (endothelial nitric oxide synthase). It was known that eNOS, which is needed for endothelial differentiation, can be transcriptionally repressed by EZH2. In turn, miR-214 targets EZH2 for inhibition. We newly found that in ESC-ECs, BDNF increases miR-214 expression, reduces EZH2 occupancy of the eNOS promoter, and increases eNOS expression. Moreover, we found that NRP-1 (neuropilin 1), KDR (kinase insert domain receptor), and pCas130 (p130 Crk-associated substrate kinase), which reportedly induce definitive endothelial differentiation of pluripotent cells, were increased in BDNF-conditioned ESC-EC. Mechanistically, miR-214 mediated the BDNF-induced expressional changes, contributing to BDNF-driven endothelial differentiation. Finally, BDNF-conditioned ESC-ECs promoted angiogenesis in vitro and in vivo. Conclusions- BDNF promotes ESC-endothelial differentiation acting via miR-214.

Publication DOI: https://doi.org/10.1161/ATVBAHA.118.311400
Divisions: College of Health & Life Sciences > Aston Medical School
Additional Information: © 2018 The Authors. Arteriosclerosis, Thrombosis, and Vascular Biology is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
Uncontrolled Keywords: Animals,Brain-Derived Neurotrophic Factor/pharmacology,Cell Differentiation/drug effects,Cell Line,Crk-Associated Substrate Protein/metabolism,Embryonic Stem Cells/physiology,Endothelial Cells/physiology,Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors,Immunophilins/metabolism,Mice,MicroRNAs/metabolism,Muscle, Smooth, Vascular/cytology,Myocytes, Smooth Muscle/metabolism,Neovascularization, Physiologic,Nerve Growth Factors/pharmacology,Nitric Oxide Synthase Type III/metabolism,Vascular Endothelial Growth Factor Receptor-2/metabolism
Publication ISSN: 1524-4636
Full Text Link:
Related URLs: https://www.aha ... BAHA.118.311400 (Publisher URL)
PURE Output Type: Article
Published Date: 2018-07-26
Accepted Date: 2018-07-02
Authors: Descamps, Betty
Saif, Jaimy
Benest, Andrew V
Biglino, Giovanni
Bates, David O
Chamorro-Jorganes, Aranzazu
Emanueli, Costanza

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