A role for Wnt signalling in self-renewal of haematopoietic stem cells
A role for Wnt signalling in self-renewal of haematopoietic stem cells
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DOI：
10.1038/nature01593
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发表时间：
2003-05-22
期刊：
影响因子：
64.8
通讯作者：
Weissman, IL
中科院分区：
文献类型：
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作者：
Reya, T;Duncan, AW;Weissman, IL
造血干细胞（hsc）具有自我更新和产生所有血统的血液的能力；然而，调控造血干细胞自我更新的信号仍不清楚。我们发现Wnt信号通路在这一过程中起着重要作用。活化β -连环蛋白的过度表达通过表型和功能扩大了长期培养的造血干细胞池。此外，造血干细胞在其正常微环境中激活了一个LEF-1/TCF报告细胞，这表明造血干细胞在体内对Wnt信号传导有反应。为了证明这一途径对HSC增殖的生理意义，我们发现轴蛋白或卷曲的配体结合域（Wnt信号通路的抑制剂）的异位表达导致体外HSC生长受到抑制，体内重建减少。此外，造血干细胞中Wnt信号的激活诱导HoxB4和Notch1的表达增加，这些基因先前与造血干细胞的自我更新有关。我们得出结论，Wnt信号通路对体外和体内正常的HSC稳态至关重要，并提供了对HSC发育调控的潜在分子层次的见解。
Haematopoietic stem cells (HSCs) have the ability to renew themselves and to give rise to all lineages of the blood; however, the signals that regulate HSC self-renewal remain unclear. Here we show that the Wnt signalling pathway has an important role in this process. Overexpression of activated beta-catenin expands the pool of HSCs in long-term cultures by both phenotype and function. Furthermore, HSCs in their normal microenvironment activate a LEF-1/TCF reporter, which indicates that HCSs respond to Wnt signalling in vivo. To demonstrate the physiological significance of this pathway for HSC proliferation we show that the ectopic expression of axin or a frizzled ligand-binding domain, inhibitors of the Wnt signalling pathway, leads to inhibition of HSC growth in vitro and reduced reconstitution in vivo. Furthermore, activation of Wnt signalling in HSCs induces increased expression of HoxB4 and Notch1, genes previously implicated in self-renewal of HSCs. We conclude that the Wnt signalling pathway is critical for normal HSC homeostasis in vitro and in vivo, and provide insight into a potential molecular hierarchy of regulation of HSC development.