Haematopoietic stem cells retain long-term repopulating activity and multipotency in the absence of stem-cell leukaemia SCL/tal-1 gene
Haematopoietic stem cells retain long-term repopulating activity and multipotency in the absence of stem-cell leukaemia SCL/tal-1 gene
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DOI：
10.1038/nature01345
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发表时间：
2003-01-30
期刊：
影响因子：
64.8
通讯作者：
Orkin, SH
中科院分区：
文献类型：
--
作者：
Mikkola, HKA;Klintman, J;Orkin, SH
血细胞的产生在个体的一生中由造血干细胞 (HSC) 维持(1)。胚胎发育过程中中胚层 HSC 的特化需要干细胞白血病 SCL/tal-1 基因产物 (2-6)。 SCL/tal-1 的强制表达会强烈诱导胚胎中的血液形成，表明该基因在造血过程中起主导作用(7,8)。在成人造血系统中，SCL/tal-1 在 HSC 和多能祖细胞以及红系和巨核细胞谱系中表达丰富 (9-11)，这与该因子在成人造血中的作用一致。在这里，我们通过条件基因打靶评估 HSC 的身份和功能是否持续需要 SCL/tal-1。我们发现SCL/tal-1对于HSC的植入、自我更新和分化为骨髓和淋巴谱系是可有可无的；然而，红细胞和巨核细胞前体细胞的正确分化取决于 SCL/tal-1。因此，SCL/tal-1对于HSC的发生至关重要，但其持续表达对于HSC的功能并不是必需的。这些发现与谱系选择机制形成鲜明对比，在谱系选择机制中，造血谱系的身份需要连续的转录因子表达(12,13)。
The production of blood cells is sustained throughout the lifetime of an individual by haematopoietic stem cells (HSCs)(1). Specification of HSCs from mesoderm during embryonic development requires the stem cell leukaemia SCL/tal-1 gene product(2-6). Forced expression of SCL/tal-1 strongly induces blood formation in embryos, indicating that this gene has a dominant role in commitment to haematopoiesis(7,8). In the adult haematopoietic system, expression of SCL/tal-1 is enriched in HSCs and multipotent progenitors, and in erythroid and megakaryocytic lineages(9-11), consistent with roles for this factor in adult haematopoiesis. Here we assess by conditional gene targeting whether SCL/tal-1 is required continuously for the identity and function of HSCs. We find that SCL/tal-1 is dispensable for HSC engraftment, self-renewal and differentiation into myeloid and lymphoid lineages; however, the proper differentiation of erythroid and megakaryocytic precursors is dependent on SCL/tal-1. Thus, SCL/tal-1 is essential for the genesis of HSCs, but its continued expression is not essential for HSC functions. These findings contrast with lineage choice mechanisms, in which the identity of haematopoietic lineages requires continuous transcription factor expression(12,13).