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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)

Research output: Contribution to journalArticle

  • Betty Descamps
  • Jaimy Saif
  • AV Benest
  • Giovanni Biglino
  • Dave Bates
  • A Chamorro-Jorganes
  • Costanza Emanueli
Original languageEnglish
Pages (from-to)2117-2125
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume38
Issue number9
Early online date26 Jul 2018
DOIs
DateAccepted/In press - 2 Jul 2018
DateE-pub ahead of print - 26 Jul 2018
DatePublished (current) - Sep 2018

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.

    Research areas

  • microRNAs, brain-derived neurotrophic factor, endothelial differentiation, embryonic stem cells, angiogenesis

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via AHA at https://www.ahajournals.org/doi/10.1161/ATVBAHA.118.311400 . Please refer to any applicable terms of use of the publisher.

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