Clonal Analysis Unveils Self-Renewing Lineage-Restricted Progenitors Generated Directly from Hematopoietic Stem Cells
Clonal Analysis Unveils Self-Renewing Lineage-Restricted Progenitors Generated Directly from Hematopoietic Stem Cells
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DOI：
10.1016/j.cell.2013.08.007
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发表时间：
2013-08-29
期刊：
影响因子：
64.5
通讯作者：
Nakauchi, Hiromitsu
中科院分区：
文献类型：
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作者：
Yamamoto, Ryo;Morita, Yohei;Nakauchi, Hiromitsu
共识认为，造血干细胞（hsc）产生自我更新能力降低的多能祖细胞（MPPs）， MPPs最终以逐步的方式产生谱系承诺的祖细胞。使用单细胞移植系统和标记小鼠，我们意外地发现了具有长期再填充活性（MyRPs）的骨髓限制性祖细胞，这些祖细胞在表型定义的HSC室中与HSC一起具有巨核细胞、巨核细胞-红细胞或普通髓细胞（分别为MkRPs、MERPs或CMRPs）的谱系。结合移植的配对子细胞实验显示，造血干细胞可以通过对称分裂产生造血干细胞，也可以通过不对称分裂直接分化为MyRPs（产生造血干细胞- mkrp或造血干细胞- cmrp对）。这些髓系旁路通路对于消融应激的快速反应至关重要。我们的研究结果表明，自我更新的丧失和通过特定分化阶段的逐步进展对造血干细胞的谱系承诺不是必需的，并提出了一种修订的造血分化模型。
Consensus holds that hematopoietic stem cells (HSCs) give rise to multipotent progenitors (MPPs) of reduced self-renewal potential and that MPPs eventually produce lineage-committed progenitor cells in a stepwise manner. Using a single-cell transplantation system and marker mice, we unexpectedly found myeloid-restricted progenitors with long-term repopulating activity (MyRPs), which are lineage-committed to megakaryocytes, megakaryocyte-erythroid cells, or common myeloid cells (MkRPs, MERPs, or CMRPs, respectively) in the phenotypically defined HSC compartment together with HSCs. Paired daughter cell assays combined with transplantation revealed that HSCs can give rise to HSCs via symmetric division or directly differentiate into MyRPs via asymmetric division (yielding HSC-MkRP or HSC-CMRP pairs). These myeloid bypass pathways could be essential for fast responses to ablation stress. Our results show that loss of self-renewal and stepwise progression through specific differentiation stages are not essential for lineage commitment of HSCs and suggest a revised model of hematopoietic differentiation.