Musashi-2 attenuates AHR signalling to expand human haematopoietic stem cells.
Musashi-2 attenuates AHR signalling to expand human haematopoietic stem cells.
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DOI：
10.1038/nature17665
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发表时间：
2016-04-28
期刊：
影响因子：
64.8
通讯作者：
Hope KJ
中科院分区：
文献类型：
--
作者：
Rentas S;Holzapfel N;Belew MS;Pratt G;Voisin V;Wilhelm BT;Bader GD;Yeo GW;Hope KJ
脐带血（CB）衍生的造血干细胞（HSC）在许多挽救生命的再生疗法中是必不可少的，但尽管它们在移植过程中提供了优势，但它们在CB单位中的低数量显著限制了它们的临床应用。已经鉴定了在培养物中增强造血干细胞和祖细胞（HSPC）扩增的选择性小分子，然而，在许多情况下，对它们的作用机制或它们所影响的途径的性质知之甚少。更深入地了解支持独特的人类HSC自我更新计划的分子途径，将有助于开发有针对性的策略，扩大这些关键细胞类型的再生疗法。尽管转录因子网络已被证明影响人类HSC的自我更新和谱系决定，但指导HSC命运的转录后机制尚未得到密切研究。在这里，我们发现RNA结合蛋白（RBP）Musashi-2（MSI 2）的过表达诱导多种促自我更新表型，包括短期再生细胞的17倍增加和长期再生HSC的净23倍体外扩增。通过对MSI 2-RNA相互作用进行全面分析，我们确定MSI 2通过转录后下调CB HSPC中的经典AHR途径组分直接减弱芳烃受体（AHR）信号传导。我们的研究为RBP控制的RNA网络提供了新的机制见解，这些网络是自我更新过程的基础，并证明离体操纵这些网络可以提供一种新的手段来增强人类HSC的再生潜力。
Umbilical cord blood (CB)-derived hematopoietic stem cells (HSCs) are essential in many life saving regenerative therapies, but their low number in CB units has significantly restricted their clinical use despite the advantages they provide during transplantation. Select small molecules that enhance hematopoietic stem and progenitor cell (HSPC) expansion in culture have been identified, however, in many cases their mechanisms of action or the nature of the pathways they impinge on are poorly understood. A greater understanding of the molecular pathways that underpin the unique human HSC self-renewal program will facilitate the development of targeted strategies that expand these critical cell types for regenerative therapies. Whereas transcription factor networks have been shown to influence the self-renewal and lineage decisions of human HSCs, the post-transcriptional mechanisms guiding HSC fate have not been closely investigated. Here we show that overexpression of the RNA-binding protein (RBP) Musashi-2 (MSI2) induces multiple pro-self-renewal phenotypes, including a 17-fold increase in short-term repopulating cells and a net 23-fold ex vivo expansion of long-term repopulating HSCs. By performing a global analysis of MSI2-RNA interactions, we determined that MSI2 directly attenuates aryl hydrocarbon receptor (AHR) signaling through post-transcriptional downregulation of canonical AHR pathway components in CB HSPCs. Our study provides new mechanistic insight into RBP-controlled RNA networks that underlie the self-renewal process and give evidence that manipulating such networks ex vivo can provide a novel means to enhance the regenerative potential of human HSCs.