期刊
STEM CELLS TRANSLATIONAL MEDICINE
卷 4, 期 10, 页码 1234-1245出版社
WILEY
DOI: 10.5966/sctm.2015-0049
关键词
Immunogenicity of human embryonic stem cells; beta(2)-Microglobulin gene targeting strategy; Human leukocyte antigen class I; Differentiation and characterization
资金
- Nancy and Clive Runnells Embryonic Stem Cell Research Fund
- U.S. Public Health Service National Institutes Health [R21 HL102833-01]
- University of Texas Medical School Bridging Grant Program
- Welch Foundation Endowment Fund [7712]
- Hans J. Muller-Eberhard and Irma Gigli Distinguished Chair in Immunology
Human embryonic stem cells (hESCs) are a promising source of cells for tissue regeneration, yet histoincompatibility remains a major challenge to their clinical application. Because the human leukocyte antigen class I (HLA-I) molecules are the primary mediators of immune rejection, we hypothesized that cells derived from a hESC line lacking HLA-I expression could be transplanted without evoking a robust immune response from allogeneic recipients. In the present study, we used the replacement targeting strategy to delete exons 2 and 3 of beta(2)-microglobulin on both gene alleles in hESCs. Because beta(2)-microglobulin serves as the HLA-I light chain, disruption of the beta(2)-microglobulin gene led to complete HLA-I deficiency on the cell surface of hESCs and their derivatives. Therefore, these cells were resistant to CD8(+) T-cell-mediated destruction. Although interferon-gamma (IFN-gamma) treatment significantly induced beta(2)-microglobulin expression, promoting CD8(+) T cell-mediated killing of control hESCs and their derivatives, CD8(+) T-cell-mediated cytotoxicity was barely observed with beta(2)-microglobulin-null hESCs and their derivatives treated with IFN-gamma. This genetic manipulation to disrupt HLA-I expression did not affect the self-renewal capacity, genomic stability, or pluripotency of hESCs. Despite being relatively sensitive to natural killer (NK) cell-mediated killing due to the lack of HLA-I expression, when transplanted into NK cell-depleted immunocompetent mice, beta(2)-microglobulin-null hESCs developed into tumors resembling those derived from control hESCs in severe combined immunodeficiency mice. These results demonstrate that beta(2)-microglobulin-null hESCs significantly reduce immunogenicity to CD8(+) T cells and might provide a renewable source of cells for tissue regeneration without the need for HLA matching in the future. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:1234-1245
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