High Levels of Canonical Wnt Signaling Lead to Loss of Stemness and Increased Differentiation in Hematopoietic Stem Cells.
High Levels of Canonical Wnt Signaling Lead to Loss of Stemness and Increased Differentiation in Hematopoietic Stem Cells.
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DOI：
10.1016/j.stemcr.2016.04.009
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发表时间：
2016-05-10
影响因子：
5.9
通讯作者：
Staal FJT
中科院分区：
文献类型：
--
作者：
Famili F;Brugman MH;Taskesen E;Naber BEA;Fodde R;Staal FJT
规范的Wnt信号调节大多数干细胞系统的自我更新。在血液系统中，Wnt信号的作用一直是争论的主题，但已有共识认为高Wnt信号会导致重建能力的丧失。为了更好地理解这一现象，我们利用了一系列亚形态突变的APC等位基因，导致了造血干细胞(HSCs)中广泛的Wnt剂量，并进行了全基因组基因表达分析。基因表达谱和功能研究表明，具有APC突变的HSCs导致Wnt水平升高、分化增强、增殖抑制但不影响凋亡，共同导致茎的丧失。因此，我们提供了对APC突变和Wnt信号在HSC生物学中的作用的机械性见解。随着Wnt信号在各种HSCs体内和体外扩增方案中的探索，我们的发现也具有临床意义。对不同Wnt剂量的小鼠HSCs进行了基因表达谱分析，GSEA显示干性基因丢失，分化增强，凋亡没有变化。功能实验证实缺乏凋亡和促进分化缺乏重建主要是由于失去真正的干细胞活性造成的。在本文中，Staal和他的同事们证明，APC肿瘤抑制基因的丢失，导致高Wnt水平，导致HSCs的重建丧失，原因是分化增强和干细胞特性的丧失。
Canonical Wnt signaling regulates the self-renewal of most if not all stem cell systems. In the blood system, the role of Wnt signaling has been the subject of much debate but there is consensus that high Wnt signals lead to loss of reconstituting capacity. To better understand this phenomenon, we have taken advantage of a series of hypomorphic mutant Apc alleles resulting in a broad range of Wnt dosages in hematopoietic stem cells (HSCs) and performed whole-genome gene expression analyses. Gene expression profiling and functional studies show that HSCs with APC mutations lead to high Wnt levels, enhanced differentiation, and diminished proliferation but have no effect on apoptosis, collectively leading to loss of stemness. Thus, we provide mechanistic insight into the role of APC mutations and Wnt signaling in HSC biology. As Wnt signals are explored in various in vivo and ex vivo expansion protocols for HSCs, our findings also have clinical ramifications. Gene expression profiling of mouse HSCs with various Wnt dosages was performed GSEA reveals loss of stemness genes, enhanced differentiation, no changes in apoptosis Functional experiments confirm the lack of apoptosis and enhanced differentiation Lack of reconstitution is mainly caused by loss of bona fide stem cell activity In this article, Staal and colleagues show that loss of the APC tumor suppressor gene, resulting in high Wnt levels, leads to loss of reconstitution by HSCs due to enhanced differentiation and loss of stem cell properties.