Hematopoiesis by iPSC-derived hematopoietic stem cells of aplastic anemia that escape cytotoxic T-cell attack

Blood Advances
J Luis EspinozaShinji Nakao

Abstract

Hematopoietic stem cells (HSCs) that lack HLA-class I alleles as a result of copy-number neutral loss of heterozygosity of the short arm of chromosome 6 (6pLOH) or HLA allelic mutations often constitute hematopoiesis in patients with acquired aplastic anemia (AA), but the precise mechanisms underlying clonal hematopoiesis induced by these HLA-lacking (HLA-) HSCs remain unknown. To address this issue, we generated induced pluripotent stem cells (iPSCs) from an AA patient who possessed HLA-B4002-lacking (B4002-) leukocytes. Three different iPSC clones (wild-type [WT], 6pLOH+, and B*40:02-mutant) were established from the patient's monocytes. Three-week cultures of the iPSCs in the presence of various growth factors produced hematopoietic cells that make up 50% to 70% of the CD34+ cells of each phenotype. When 106 iPSC-derived CD34+ (iCD34+) cells with the 3 different genotypes were injected into the femoral bone of C57BL/6.Rag2 mice, 2.1% to 7.3% human multilineage CD45+ cells of each HLA phenotype were detected in the bone marrow, spleen, and peripheral blood of the mice at 9 to 12 weeks after the injection, with no significant difference in the human:mouse chimerism ratio among the 3 groups. Stimulation of the patient's CD8+ T ...Continue Reading

References

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Citations

Jul 6, 2018·British Journal of Haematology·Lucio Luzzatto, Antonio M Risitano
Apr 21, 2020·British Journal of Haematology·Yoshitaka ZaimokuNeal S Young
Oct 17, 2018·Frontiers in Immunology·Huensuk Kim, Christoph Schaniel
Mar 4, 2021·Immunity, Inflammation and Disease·Bingnan LiuRong Fu
Mar 7, 2020·Cell Stem Cell·Arun SharmaClive N Svendsen

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