Abstract
Early B-cell factor-1 (EBF1) is a transcription factor with an important role in cell lineage specification and commitment during the early stage of cell maturation. Originally described during B-cell maturation, EBF1 was subsequently identified as a crucial molecule for proper cell fate commitment of mesenchymal stem cells into adipocytes, osteoblasts and muscle cells. In vessels, EBF1 expression and function have never been documented. Our data indicate that EBF1 is highly expressed in peri-endothelial cells in both tumor vessels and in physiological conditions. Immunohistochemistry, quantitative reverse transcription polymerase chain reaction (RT-qPCR) and fluorescence-activated cell sorting (FACS) analysis suggest that EBF1-expressing peri-endothelial cells represent bona fide pericytes and selectively express well-recognized markers employed in the identification of the pericyte phenotype (SMA, PDGFRβ, CD146, NG2). This observation was also confirmed in vitro in human placenta-derived pericytes and in human brain vascular pericytes (HBVP). Of note, in accord with the key role of EBF1 in the cell lineage commitment of mesenchymal stem cells, EBF1-silenced HBVP cells showed a significant reduction in PDGFRβ and CD146, but not CD90, a marker mostly associated with a prominent mesenchymal phenotype. Moreover, the expression levels of VEGF, angiopoietin-1, NG2 and TGF-β, cytokines produced by pericytes during angiogenesis and linked to their differentiation and activation, were also significantly reduced. Overall, the data suggest a functional role of EBF1 in the cell fate commitment toward the pericyte phenotype.
Highlights
B-cell factor 1 (EBF1) represents a highly evolutionarily conserved DNA-binding transcription factor with an atypical zinc-finger and helix-loop-helix motif that belongs to a family of four genes (Liao 2009) with an important role in cellular differentiation during the development of different tissues (Medina et al 2004; Busslinger et al 2000; Liberg et al 2002)
To assess whether Early B-cell factor 1 (EBF1) is expressed in vessels in physiological and/or pathological non-neoplastic conditions, we investigated EBF1 expression on representative sections from different normal tissues and in representative non-neoplastic conditions where angiogenesis is active
Pericytes are an essential component of the vascular unit, with an important functional role in angiogenesis, vessel stability and homeostasis
Summary
B-cell factor 1 (EBF1) represents a highly evolutionarily conserved DNA-binding transcription factor with an atypical zinc-finger and helix-loop-helix motif that belongs to a family of four genes (ebf, ebf, ebf, ebf4) (Liao 2009) with an important role in cellular differentiation during the development of different tissues (Medina et al 2004; Busslinger et al 2000; Liberg et al 2002). (Armulik et al 2011, 2010) Their function is not completely clarified, pericytes have an important role in different processes including the regulation of blood flow (Kutcher et al 2009) and the maintenance of the blood–brain barrier (Armulik et al 2010). Pericytes exert an important function in vascular development, interacting with endothelial cells through a dynamic and complex paracrine cross-talk. MSCs and pericytes share the same embryological origin, and pericytes themselves are thought to derive from mesodermal progenitors (Armulik et al 2011). Since EBFs have been described as major regulators of MSC differentiation (Kiviranta et al 2013), we investigated whether EBF expression allows for the selective discrimination of pericytes from MSCs
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