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首页> 外文期刊>The journal of clinical investigation >Congenital amegakaryocytic thrombocytopenia iPS cells exhibit defective MPL-mediated signaling
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Congenital amegakaryocytic thrombocytopenia iPS cells exhibit defective MPL-mediated signaling

机译：先天性巨核细胞血小板减少症iPS细胞表现出有缺陷的MPL介导的信号

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Congenital amegakaryocytic thrombocytopenia (CAMT) is caused by the loss of thrombopoietin receptor–mediated (MPL-mediated) signaling, which causes severe pancytopenia leading to bone marrow failure with onset of thrombocytopenia and anemia prior to leukopenia. Because Mpl~(–/–) mice do not exhibit the human disease phenotype, we used an in vitro disease tracing system with induced pluripotent stem cells (iPSCs) derived from a CAMT patient (CAMT iPSCs) and normal iPSCs to investigate the role of MPL signaling in hematopoiesis. We found that MPL signaling is essential for maintenance of the CD34~(+) multipotent hematopoietic progenitor (MPP) population and development of the CD41~(+)GPA~(+) megakaryocyte-erythrocyte progenitor (MEP) population, and its role in the fate decision leading differentiation toward megakaryopoiesis or erythropoiesis differs considerably between normal and CAMT cells. Surprisingly, complimentary transduction of MPL into normal or CAMT iPSCs using a retroviral vector showed that MPL overexpression promoted erythropoiesis in normal CD34~(+) hematopoietic progenitor cells (HPCs), but impaired erythropoiesis and increased aberrant megakaryocyte production in CAMT iPSC–derived CD34~(+) HPCs, reflecting a difference in the expression of the transcription factor FLI1 . These results demonstrate that impaired transcriptional regulation of the MPL signaling that normally governs megakaryopoiesis and erythropoiesis underlies CAMT.
机译：先天性巨核细胞血小板减少症（CAMT）是由血小板生成素受体介导的（MPL介导的）信号丢失引起的，该信号导致严重的全血细胞减少症，导致骨髓衰竭，并伴有白细胞减少症和血小板减少症和贫血。由于Mpl〜（– / –）小鼠未表现出人类疾病表型，因此我们使用了体外疾病追踪系统，该系统使用了来自CAMT患者（CAMT iPSC）和正常iPSC的诱导性多能干细胞（iPSC）。造血过程中的MPL信号传导。我们发现MPL信号对于维持CD34〜（+）多能造血祖细胞（MPP）和CD41〜（+）GPA〜（+）巨核细胞-红细胞祖细胞（MEP）的发育至关重要，并且在导致正常细胞和CAMT细胞分化为巨核细胞或红细胞生成的决定。出乎意料的是，使用逆转录病毒载体将MPL互补转导至正常或CAMT iPSC中，表明MPL过表达促进正常CD34〜（+）造血祖细胞（HPC）中的红细胞生成，但损害了红细胞生成并增加了CAMT iPSC〜衍生的巨核细胞的异常生成（+）HPC，反映了转录因子FLI1表达的差异。这些结果表明，正常支配巨核细胞生成和红细胞生成的MPL信号的转录调控受损是CAMT的基础。

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