Abstract
Endothelial colony forming cells (ECFC) or late blood outgrowth endothelial cells (BOEC) have been proposed to contribute to neovascularization in humans. Exploring genes characteristic for the progenitor status of ECFC we have identified the forkhead box transcription factor FOXF1 to be selectively expressed in ECFC compared to mature endothelial cells isolated from the vessel wall. Analyzing the role of FOXF1 by gain- and loss-of-function studies we detected a strong impact of FOXF1 expression on the particularly high sprouting capabilities of endothelial progenitors. This apparently relates to the regulation of expression of several surface receptors. First, FOXF1 overexpression specifically induces the expression of Notch2 receptors and induces sprouting. Vice versa, knock-down of FOXF1 and Notch2 reduces sprouting. In addition, FOXF1 augments the expression of VEGF receptor-2 and of the arterial marker ephrin B2, whereas it downmodulates the venous marker EphB4. In line with these findings on human endothelial progenitors, we further show that knockdown of FOXF1 in the zebrafish model alters, during embryonic development, the regular formation of vasculature by sprouting. Hence, these findings support a crucial role of FOXF1 for endothelial progenitors and connected vascular sprouting as it may be relevant for tissue neovascularization. It further implicates Notch2, VEGF receptor-2, and ephrin B2 as downstream mediators of FOXF1 functions.
Highlights
Endothelial colony forming cells (ECFC), termed blood outgrowth endothelial cells (BOEC), can be outgrown from human cord blood or adult peripheral blood using standard endothelial cell growth conditions (Yoder et al, 2007; Martin-Ramirez et al, 2012; Hofer-Warbinek et al, 2014; Medina et al, 2017)
To decipher genes expressed in endothelial progenitors of the ECFC type we have comparatively analyzed gene expression profiles of ECFC isolated from blood and of terminally differentiated endothelial cells of the vessel wall
When focusing our analysis on transcriptional regulators, we found two transcription factors more than 5-fold overrepresented in the ECFC of both sources, the winged helix transcription factor FOXF1 and the Krueppelrelated zinc finger protein 117 (Supplemental Table S1)
Summary
Endothelial colony forming cells (ECFC), termed blood outgrowth endothelial cells (BOEC), can be outgrown from human cord blood or adult peripheral blood using standard endothelial cell growth conditions (Yoder et al, 2007; Martin-Ramirez et al, 2012; Hofer-Warbinek et al, 2014; Medina et al, 2017). In distinction from other so-called circulating endothelial progenitor cells (EPC), that can be obtained from blood by different isolation and culture conditions and are of hematopoietic origin, ECFC have characteristics of true endothelial progenitors They form vascular networks and integrate into newly formed vessels in vivo (Dubois et al, 2010; Banno and Yoder, 2017). ECFC are difficult to obtain from murine blood, an endothelial progenitor/stem-like cell population has been located at the inner surface of murine blood vessels (Naito et al, 2012)
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