Abstract
BackgroundHuman embryonic stem cells (hESCs) are an attractive resource for new therapeutic approaches that involve tissue regeneration. hESCs have exhibited low immunogenicity due to low levels of Mayor Histocompatibility Complex (MHC) class-I and absence of MHC class-II expression. Nevertheless, the mechanisms regulating MHC expression in hESCs had not been explored.Methodology/Principal FindingsWe analyzed the expression levels of classical and non-classical MHC class-I, MHC class-II molecules, antigen-processing machinery (APM) components and NKG2D ligands (NKG2D-L) in hESCs, induced pluripotent stem cells (iPSCs) and NTera2 (NT2) teratocarcinoma cell line. Epigenetic mechanisms involved in the regulation of these genes were investigated by bisulfite sequencing and chromatin immunoprecipitation (ChIP) assays. We showed that low levels of MHC class-I molecules were associated with absent or reduced expression of the transporter associated with antigen processing 1 (TAP-1) and tapasin (TPN) components in hESCs and iPSCs, which are involved in the transport and load of peptides. Furthermore, lack of β2-microglobulin (β2m) light chain in these cells limited the expression of MHC class I trimeric molecule on the cell surface. NKG2D ligands (MICA, MICB) were observed in all pluripotent stem cells lines. Epigenetic analysis showed that H3K9me3 repressed the TPN gene in undifferentiated cells whilst HLA-B and β2m acquired the H3K4me3 modification during the differentiation to embryoid bodies (EBs). Absence of HLA-DR and HLA-G expression was regulated by DNA methylation.Conclusions/SignificanceOur data provide fundamental evidence for the epigenetic control of MHC in hESCs and iPSCs. Reduced MHC class I and class II expression in hESCs and iPSCs can limit their recognition by the immune response against these cells. The knowledge of these mechanisms will further allow the development of strategies to induce tolerance and improve stem cell allograft acceptance.
Highlights
Human embryonic stem cells are pluripotent cells derived from the inner cell mass of blastocysts. hESCs have the capacity to differentiate into all tissues of the body, making them useful in regenerative medicine
The expression of Mayor Histocompatibility Complex (MHC) class I and class II molecules was analyzed in undifferentiated human embryonic stem cell line Shef1 and teratocarcioma cell line NT2 by real-time RT-PCR and flow-cytometry
Analysis of the antigen processing machinery (APM) components revealed that, the transporter molecules transporter associated with antigen processing 1 (TAP-1) and TAP-2 were absent or weakly detected in Shef-1 and NT2 stem cell lines (Fig. 1B). hESC lacked expression of Tapasin (TPN) and Calreticulin (CLR), which are involved in the correct folding of MHC class I molecules, but these molecules were detected at normal levels in the NT2 cell line
Summary
Human embryonic stem cells (hESCs) are pluripotent cells derived from the inner cell mass of blastocysts. hESCs have the capacity to differentiate into all tissues of the body, making them useful in regenerative medicine. Human embryonic stem cells (hESCs) are pluripotent cells derived from the inner cell mass of blastocysts. Work showed that hESCs express very low levels of MHC class I molecules on the cell surface and fail to elicit immune responses in immune-competent mice [1], supporting the hypothesis that these cells have immune-privilege properties which expands their use in cell replacement therapy [2,3,4,5]. The lack of human lymphocyte antigen (HLA)-A, -B, and MHC class II expression in trophoblast cells provide mechanisms by which these cells escape maternal immune recognition [6]. Human embryonic stem cells (hESCs) are an attractive resource for new therapeutic approaches that involve tissue regeneration. HESCs have exhibited low immunogenicity due to low levels of Mayor Histocompatibility Complex (MHC) class-I and absence of MHC class-II expression. The mechanisms regulating MHC expression in hESCs had not been explored
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