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    • br Introduction Adipose tissue derived

    2018-11-06


    Introduction Adipose tissue-derived stromal ctap (ASCs) have been reported to diverge under specific culture conditions towards adipogenic, chondrogenic, myogenic and osteogenic cells (Zuk et al., 2001). This apparent plasticity, combined with the fact that these cells can be isolated in high numbers by minimally invasive methods, raised great interest in ASCs as a source of autologous cells for use in regenerative medicine. The use of ASCs in cardiovascular repair has been the subject of several in vitro- and animal studies and has moved towards clinical applications. Administration of adipose-derived cells, either freshly isolated or after conditioning in cell culture, was shown to improve left ventricular function in models of acute and chronic myocardial infarction. Likewise, in animal models of hind limb ischemia, favorable effects on revascularization have been reported (reviewed by Madonna et al. (2009)). The mechanisms through which ASCs exert these effects are not fully elucidated. ASCs have been reported to differentiate both in vitro and in vivo towards cardiomyocytic or endothelial phenotypes. In animal models it was observed that at least a part of the administered ASCs actually displays cardiomyocytic or endothelial markers and becomes structurally incorporated in the myocardium or vascular structures, respectively (Miranville et al., 2004; Planat-Benard et al., 2004; Yamada et al., 2006; Miyahara et al., 2006). In addition, it was shown that ASCs can function as a paracrine source of growth factors, cytokines and signaling molecules (Miyahara et al., 2006; Kondo et al., 2009). Thus, the view has emerged that ASCs support cardiovascular repair by providing local signals for cell recruitment and tissue survival as well as by physically substituting, in an adaptive manner, for lost cells. Several papers describe attempts to specifically differentiate ASCs towards an endothelial phenotype (Miranville et al., 2004; Planat-Benard et al., 2004; Wosnitza et al., 2007; Kang et al., 2010; Konno et al., 2010). In vitro culture of ASCs in media supplemented with specific growth factors, in particular VEGF and bFGF, resulted in the expression of a limited range of endothelial markers, mostly with incomplete penetrance. In culture, cells did not display the typical endothelial morphology, nor did they organize in endothelial sheet-like structures. Therefore, the concept of conditioning ASCs to cells with an endothelial phenotype by stimulation with growth factors has proven partially successful but seems to require further optimization. Sry-related high-mobility-group box (SOX) transcription factors are involved in maintaining stemness, differentiation and lineage commitment. Development of the vasculature is critically dependent on the SOXF subfamily, consisting of SOX7, SOX17 and SOX18 (Lefebvre et al., 2007; François et al., 2010). During mouse embryonic development, SOX18 is expressed in the developing cardiovascular system: in the allantois and yolk sac blood islands, in the developing heart and in the paired dorsal aorta. Expression is continued at sites of embryonal angiogenic- and vasculogenic expansion and was reported to re-occur in adult skin wounding (Pennisi et al., 2000a; Darby et al., 2001). In animal models, SOX7, SOX17 and SOX18 were found to have essential, partly redundant, roles in the formation of the vasculature during embryonic development (Pennisi et al., 2000b; François et al., 2008; Sakamoto et al., 2007; Herpers et al., 2008; Pendeville et al., 2008; Cermenati et al., 2008; Matsui et al., 2006; Sacilotto et al., 2013). However, their effects at the level of gene regulation and, thus, the molecular basis of their role in development are poorly understood. Applying overexpression and silencing of SOX18 in endothelial cells, our group has shown that SOX18 has a crucial role in both the transcription of the endothelial-specific tight junction protein claudin 5 and maintenance of the endothelial barrier (Fontijn et al., 2008). Recently, Hoeth et al. (2012) analyzed the transcriptome of endothelial cells overexpressing SOX18, pointing at a role for SOX18 in the morphogenesis of the vasculature. Using defined in vitro culture methods, two populations of angiogenic cells can be isolated from blood: early EPCs that contribute to vessel repair in a paracrine manner and endothelial colony forming cells (ECFCs), or outgrowth endothelial cells (OEC, late EPC), that have the capacity to physically form neo-vessels (reviewed in Favre et al., 2013). Using comparative genome-wide transcriptional profiling of these two cell populations, Medina et al. (2010) have shown that the mRNA fingerprint of ECFC closely resembles that of endothelial cells, and is accompanied by high, specific expression of SOX18. Thus, the available literature indicates a key role for SOX18 in vascular development and repair, in both embryonic and adult stages, and in specification of the endothelial phenotype. We therefore hypothesized that ectopic expression of SOX18 in ASCs might induce endothelial-like features and tested this reprogramming approach in vitro.