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    • br Introduction Human leukocyte antigen G HLA G

    2018-11-08


    Introduction Human leukocyte antigen G (HLA-G) belongs to the non-classical HLA class I angiotensin ii and is a tolerogenic molecule that acts on cells of both innate and adaptive immunity. Besides its immunosuppressive function in transplantation, autoimmunity and tumour progression, HLA-G expression is associated with implantation and protection of the semi-allogeneic fetus from the maternal immune system (Carosella et al., 2008; Rebmann et al., 2007; Hunt et al., 2005). Trophoblast cells, which preferentially express HLA-G as well as small amounts of HLA-C, -E and -F, play a major role in tolerance, implantation and vascular remodelling (Berger et al., 2010; Ishitani et al., 2003). These cells originate from the trophectoderm (TE) cells at the blastocyst stage of embryo development, prior to implantation. Despite the essential role in implantation that has been attributed to the soluble form of HLA-G (Jurisicova et al., 1996a,b; Yao et al., 2005; Shaikly et al., 2008; Fuzzi et al., 2002), little is known about HLA-G gene expression and its molecular control during in vivo human embryogenesis. The knowledge on HLA-G and its role in implantation is largely based on in vitro co-culture studies using decidua and trophoblast tissue (Teklenburg and Macklon, 2009; Helige et al., 2008; Moser et al., 2010). Although these studies provide very valuable information, the degree to which they can be extrapolated to the human in vivo situation is limited. In previous work, we showed that both the TE and inner cell mass (ICM) cells of human full blastocysts display HLA-G on the surface membrane (Verloes et al., 2011). Interestingly, we found that during blastocyst expansion, HLA-G was down-regulated in the inner ICM cells (the precursors of the epiblast or EPI) but not in the outer ICM cells (the precursors of the hypoblast). This is in line with the fact that the HLA-G5 protein is consistently found in the mesoderm of the yolk sac, in the first hematopoietic cells of the erythroid lineage as well as in endothelial cells of developing blood vessels of the embryo/fetus, all structures originating from the hypoblast (Menier et al., 2004). As mentioned above, research on the mechanisms of control of gene-expression during human embryogenesis is limited. The main reasons for this are legal and ethical issues on one hand and the scarcity of human preimplantation material for research purposes on the other hand. Conversely, human embryonic stem cells (hESC), which are derived from blastocyst-stage ICM cells, are an interesting alternative research model for early human embryogenesis (Dvash and Benvenisty, 2004; Friedrich Ben-Nun and Benvenisty, 2006; Rubin, 2008). During our work on the expression of HLA-G in human pre-implantation embryos, we detected expression of HLA-G both at the mRNA and protein levels in three in-house derived hESC lines (Verloes et al., 2011). Intriguingly, different studies by other groups reported discrepant findings on whether HLA-G mRNA and protein are present (Verloes et al., 2011; Grinnemo et al., 2006; Marchand et al., 2011; Hanna et al., 2010) or absent in hESC (Drukker et al., 2002; Suarez-Alvarez et al., 2010; Zhu et al., 2012; Telugu et al., 2013; Li et al., 2013). These differences might be due to the significant genetic and epigenetic diversity that is found amongst different hESC lines. In turn, this diversity may be linked to the genetic and epigenetic status of the embryo that was used to derive the line or may be variation acquired during derivation and in vitro culture (Richards et al., 2004; Abeyta et al., 2004). Another likely alternative is that the differences reflect the endogenous mechanisms of gene expression control. In this context, hESC provide an interesting opportunity to investigate these mechanisms in cells closely related to those found in early human embryos. HLA-G, encoded by the major histocompatibility complex, is located on chromosome 6p21.3 and is composed of eight exons and seven introns with a stop codon at exon 6. The gene exhibits a 5′-upstream regulatory region (5′URR)/promoter extending at least 1.4kb from the ATG initiation codon and a 3′ untranslated region (3′UTR) (Solier et al., 2001; Moreau et al., 2009). At the transcriptional level, HLA-G expression is mainly controlled by its promoter.