Identification of unipotent megakaryocyte progenitors in human hematopoiesis
Identification of unipotent megakaryocyte progenitors in human hematopoiesis
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DOI：
10.1182/blood-2016-09-741611
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发表时间：
2017-06-22
期刊：
影响因子：
20.3
通讯作者：
Akashi, Koichi
中科院分区：
文献类型：
--
作者：
Miyawaki, Kohta;Iwasaki, Hiromi;Akashi, Koichi
人类巨核细胞的发育途径尚不清楚，纯单能巨核细胞祖细胞的定义仍存在争议。使用单细胞转录组分析，我们已经在未成熟的造血干细胞和祖细胞群体中鉴定出一群细胞，它们特异性地表达与巨核细胞谱系相关的基因。我们使用CD41作为阳性标记物来识别CD34(+)、CD38(+)、IL-3Rα(DIM)、CD45RA(-)普通髓系祖细胞(CMP)群体中的这些细胞。这些细胞缺乏红系和粒-巨噬细胞的潜能，但在体内和体外都表现出强烈的向巨核细胞系的高频率分化。这些细胞的效率和扩增潜力超过了传统的双能巨核/红系祖细胞。因此，CD41(+)cMP被定义为一种单核巨核系祖细胞(MegP)，它可能代表人类巨核细胞生成的主要途径，独立于典型的巨核细胞-红系分支。在原发性血小板增多症患者的骨髓中，在Janus激酶2突变的高负担的背景下，MegP群体显著扩大。因此，预期可分离的和功能均一的人MegP将有助于阐明正常和恶性人类造血的潜在机制。
The developmental pathway for human megakaryocytes remains unclear, and the definition of pure unipotent megakaryocyte progenitor is still controversial. Using single-cell transcriptome analysis, we have identified a cluster of cells within immature hematopoietic stem-and progenitor-cell populations that specifically expresses genes related to the megakaryocyte lineage. We used CD41 as a positive marker to identify these cells within the CD34(+)CD38(+)IL-3R alpha(dim)CD45RA(-) common myeloid progenitor (CMP) population. These cells lacked erythroid and granulocyte-macrophage potential but exhibited robust differentiation into the megakaryocyte lineage at a high frequency, both in vivo and in vitro. The efficiency and expansion potential of these cells exceeded those of conventional bipotent megakaryocyte/erythrocyte progenitors. Accordingly, the CD41(+) CMP was defined as a unipotent megakaryocyte progenitor (MegP) that is likely to represent the major pathway for human megakaryopoiesis, independent of canonical megakaryocyte-erythroid lineage bifurcation. In the bone marrow of patients with essential thrombocythemia, the MegP population was significantly expanded in the context of a high burden of Janus kinase 2 mutations. Thus, the prospectively isolatable and functionally homogeneous human MegP will be useful for the elucidation of the mechanisms underlying normal and malignant human hematopoiesis.