Sustained ex vivo expansion of hematopoietic stem cells mediated by thrombopoietin.
Sustained ex vivo expansion of hematopoietic stem cells mediated by thrombopoietin.
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DOI：
10.1073/pnas.96.14.8126
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发表时间：
1999-07
影响因子：
11.1
通讯作者：
M. Yagi;Kindred A. Ritchie;E. Sitnicka;C. Storey;G. Roth;S. Bartelmez
中科院分区：
文献类型：
--
作者：
M. Yagi;Kindred A. Ritchie;E. Sitnicka;C. Storey;G. Roth;S. Bartelmez
造血干细胞（HSC）被定义为一种可以自我复制或产生子细胞的细胞，这些子细胞注定会分化为不同特定谱系的成熟细胞。最原始的HSC的自我复制产生具有较长（可能无限）克隆寿命的子细胞，而HSC的分化产生的子细胞表现出克隆寿命逐渐缩短、多谱系潜力和谱系定型的丧失。先前的研究表明，HSC 离体增殖有利于分化，但牺牲了自我复制，最终导致 HSC 完全丧失。相比之下，移植研究表明，单个 HSC 可以在受到致命辐射的小鼠的骨髓中重新繁殖，这表明 HSC 在体内发生自我更新。血小板生成素 (TPO) 已被证明既可作为巨核细胞的增殖和分化因子，又可作为 HSC 的存活和弱增殖因子。我们的研究重点是外源 TPO 对小鼠长期骨髓培养物 (LTBMC) 中 HSC 的影响。之前的结果表明，在没有 TPO 的情况下，LTBMC 中的 HSC 会下降。相比之下，通过体内竞争性再增殖试验检测到，TPO 的持续存在导致长期和短期再增殖 HSC 的产生。 HSC 在 4 个月内生成，其浓度与正常骨髓相似。我们的结果表明TPO可以介导LTBMC中HSC的自我复制，并证明HSC可以离体自我复制。
The hematopoietic stem cell (HSC) is defined as a cell that can either self-replicate or generate daughter cells that are destined to commit to mature cells of different specific lineages. Self-replication of the most primitive HSC produces daughter cells that possess a long (possibly unlimited) clonal lifespan, whereas differentiation of HSC produces daughter cells that demonstrate a progressive reduction of their clonal lifespan, a loss of multilineage potential, and lineage commitment. Previous studies indicated that the proliferation of HSC ex vivo favors differentiation at the expense of self-replication, eventually resulting in a complete loss of HSC. In contrast, transplantation studies have shown that a single HSC can repopulate the marrow of a lethally irradiated mouse, demonstrating that self-renewal of HSC occurs in vivo. Thrombopoietin (TPO) has been shown to function both as a proliferative and differentiative factor for megakaryocytes and as a survival and weakly proliferative factor for HSC. Our studies focused on the effects of exogenous TPO on HSC in mouse long-term bone marrow cultures (LTBMC). Previous results indicate that HSC decline in LTBMC in the absence of TPO. In contrast, the continuous presence of TPO resulted in the generation of both long- and short-term repopulating HSC as detected by an in vivo competitive repopulation assay. HSC were generated over a 4-month period at concentrations similar to normal bone marrow. Our results demonstrate that TPO can mediate the self-replication of HSC in LTBMC, and provide proof that HSC can self-replicate ex vivo.