Signaling Via PI3K/FOXO1A Pathway Modulates Formation and Survival of Human Embryonic Stem Cell-Derived Endothelial Cells

Béla Merkely, Edit Gara, Zsuzsanna Lendvai, Judit Skopál, Thomas Leja, Wenhua Zhou, Annamária Kosztin, György Várady, Maxime Mioulane, Zsolt Bagyura, Tamás Németh, Sian E. Harding, Gábor Földes

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8 Citations (Scopus)

Abstract

Vascular derivatives of human embryonic stem cells (hESC) are being developed as sources of tissue-specific cells for organ regeneration. However, identity of developmental pathways that modulate the specification of endothelial cells is not known yet. We studied phosphatidylinositol 3-kinase (PI3K)-Forkhead box O transcription factor 1A (FOXO1A) pathways during differentiation of hESC toward endothelial lineage and on proliferation, maturation, and cell death of hESC-derived endothelial cells (hESC-EC). During differentiation of hESC, expression of FOXO1A transcription factor was linked to the expression of a cluster of angiogenesis- and vascular remodeling-related genes. PI3K inhibitor LY294002 activated FOXO1A and induced formation of CD31+ hESC-EC. In contrast, differentiating hESC with silenced FOXO1A by small interfering RNA (siRNA) showed lower mRNA levels of CD31 and angiopoietin2. LY294002 decreased proliferative activity of purified hESC-EC, while FOXO1A siRNA increased their proliferation. LY294002 inhibits migration and tube formation of hESC-EC; in contrast, FOXO1A siRNA increased in vitro tube formation activity of hESC-EC. After in vivo conditioning of cells in athymic nude rats, cells retain their low FOXO1A expression levels. PI3K/FOXO1A pathway is important for function and survival of hESC-EC and in the regulation of endothelial cell fate. Understanding these properties of hESC-EC may help in future applications for treatment of injured organs.

Original languageEnglish
Pages (from-to)869-878
Number of pages10
JournalStem Cells and Development
Volume24
Issue number7
DOIs
Publication statusPublished - Apr 1 2015

ASJC Scopus subject areas

  • Hematology
  • Developmental Biology
  • Cell Biology

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    Merkely, B., Gara, E., Lendvai, Z., Skopál, J., Leja, T., Zhou, W., Kosztin, A., Várady, G., Mioulane, M., Bagyura, Z., Németh, T., Harding, S. E., & Földes, G. (2015). Signaling Via PI3K/FOXO1A Pathway Modulates Formation and Survival of Human Embryonic Stem Cell-Derived Endothelial Cells. Stem Cells and Development, 24(7), 869-878. https://doi.org/10.1089/scd.2014.0247