| Autor: |
J. Luis Espinoza, Mahmoud I. Elbadry, Kazuhisa Chonabayashi, Yoshinori Yoshida, Takamasa Katagiri, Kenichi Harada, Noriharu Nakagawa, Yoshitaka Zaimoku, Tatsuya Imi, Hiroyuki Takamatsu, Tatsuhiko Ozawa, Hiroyuki Maruyama, Hassan A. Hassanein, Amal Khalifa A. Noreldin, Katsuto Takenaka, Koichi Akashi, Hiroshi Hamana, Hiroyuki Kishi, Yoshiki Akatsuka, Shinji Nakao |
| Jazyk: |
angličtina |
| Rok vydání: |
2018 |
| Předmět: |
|
| Zdroj: |
Blood Advances, Vol 2, Iss 4, Pp 390-400 (2018) |
| Druh dokumentu: |
article |
| ISSN: |
2473-9529 |
| DOI: |
10.1182/bloodadvances.2017013342 |
| Popis: |
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 cells with the WT iCD34+ cells generated a cytotoxic T lymphocyte (CTL) line capable of killing WT iCD34+ cells but not B4002− iCD34+ cells. These data suggest that B4002− iCD34+ cells show a repopulating ability similar to that of WT iCD34+ cells when autologous T cells are absent and CTL precursors capable of selectively killing WT HSCs are present in the patient's peripheral blood. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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