title: Human Parthenogenetic Embryonic Stem Cell-Derived Neural Stem Cells Express HLA-G and Show Unique Resistance to NK Cell-Mediated Killing.
abstract: Parent-of-origin imprints have been implicated in the regulation of neural differentiation and brain development. Previously we have shown that, despite the lack of a paternal genome, human parthenogenetic (PG) embryonic stem cells (hESCs) can form proliferating neural stem cells (NSCs) that are capable of differentiation into physiologically functional neurons while maintaining allele-specific expression of imprinted genes. Since biparental ("normal") hESC-derived NSCs (N NSCs) are targeted by immune cells, we characterized the immunogenicity of PG NSCs. Flow cytometry and immunocytochemistry revealed that both N NSCs and PG NSCs exhibited surface expression of human leukocyte antigen (HLA) class I but not HLA-DR molecules. Functional analyses using an in vitro mixed lymphocyte reaction assay resulted in less proliferation of peripheral blood mononuclear cells (PBMC) with PG compared with N NSCs. In addition, natural killer (NK) cells cytolyzed PG less than N NSCs. At a molecular level, expression analyses of immune regulatory factors revealed higher HLA-G levels in PG compared with N NSCs. In line with this finding, MIR152, which represses HLA-G expression, is less transcribed in PG compared with N cells. Blockage of HLA-G receptors ILT2 and KIR2DL4 on natural killer cell leukemia (NKL) cells increased cytolysis of PG NSCs. Together this indicates that PG NSCs have unique immunological properties due to elevated HLA-G expression.
authors: Institute for Medical Radiology and Cell Research (MSZ) in the Center for Experimental Molecular Medicine (ZEMM), University of Würzburg, Würzburg, Germany.
authors: Jessica
authors: J
authors: Schmitt
authors: Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.
authors: Sigrid
authors: S
authors: Eckardt
authors: University Children's Hospital Würzburg, Pediatric Hematology/Oncology, Würzburg, Germany.
authors: Paul G
authors: PG
authors: Schlegel
authors: Department of Neurosurgery, Section for Experimental Tumor Immunology, University of Würzburg, Würzburg, Germany.
authors: Anna-Leena
authors: AL
authors: Sirén
authors: University of Würzburg Medical School, Department of Obstetrics and Gynecology, Section for Experimental Tumor Immunology, University of Würzburg, Würzburg, Germany.
authors: Valentin S
authors: VS
authors: Bruttel
authors: Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.
authors: K John
authors: KJ
authors: McLaughlin
authors: University of Würzburg Medical School, Department of Obstetrics and Gynecology, Section for Experimental Tumor Immunology, University of Würzburg, Würzburg, Germany.
authors: Jörg
authors: J
authors: Wischhusen
authors: Institute for Medical Radiology and Cell Research (MSZ) in the Center for Experimental Molecular Medicine (ZEMM), University of Würzburg, Würzburg, Germany.
authors: Albrecht M
authors: AM
authors: Müller
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D053595:Embryonic Stem Cells / Q000166:cytology*; D015870:Gene Expression; D005786:Gene Expression Regulation; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D059951:HLA-G Antigens / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics; D058953:Neural Stem Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
chemical_list: D006684:HLA-DR Antigens; D059951:HLA-G Antigens; C550856:MIRN152 microRNA, human; D035683:MicroRNAs