摘要

Adult stem and progenitor cells are uniquely capable of self-renewal, and targeting this process represents a potential therapeutic opportunity. The early erythroid progenitor, burst-forming unit erythroid (BFU-E), has substantial self-renewal potential and serves as a key cell type for the treatment of anemias. However, our understanding of mechanisms underlying BFU-E self-renewal is extremely limited. Here, we found that the muscarinic acetylcholine receptor, cholinergic receptor, muscarinic 4 (CHRM4), pathway regulates BFU-E self-renewal and that pharmacological inhibition of CHRM4 corrects anemias of myelodysplastic syndrome (MDS), aging, and hemolysis. Genetic down-regulation of CHRM4 or pharmacologic inhibition of CHRM4 using the selective antagonist PD102807 promoted BFU-E self-renewal, whereas deletion of Chrm4 increased erythroid cell production under stress conditions in vivo. Moreover, muscarinic acetylcholine receptor antagonists corrected anemias in mouse models of MDS, aging, and hemolysis in vivo, extending the survival of mice with MDS relative to that of controls. The effects of muscarinic receptor antagonism on promoting expansion of BFU-Es were mediated by cyclic AMP induction of the transcription factor CREB, whose targets up-regulated key regulators of BFU-E self-renewal. On the basis of these data, we propose a model of hematopoietic progenitor self-renewal through a cholinergic-mediated "hematopoietic reflex" and identify muscarinic acetylcholine receptor antagonists as potential therapies for anemias associated with MDS, aging, and hemolysis.

译文

成体干细胞和祖细胞具有独特的自我更新能力,靶向这一过程代表了一个潜在的治疗机会。早期红系祖细胞,红系爆发形成单位 (BFU-E),具有巨大的自我更新潜力,是治疗贫血的关键细胞类型。然而,我们对 BFU-E 自我更新机制的理解极其有限。在这里,我们发现 m 受体,胆碱能受体,m 受体 4 (CHRM4), 通路调节 BFU-E 自我更新,CHRM4 的药理抑制纠正骨髓增生异常综合征 (MDS) 、衰老和溶血的贫血。使用选择性拮抗剂 PD102807 的 CHRM4 的遗传下调或 CHRM4 的药理抑制促进了 BFU-E 的自我更新,而 Chrm4 的缺失增加了体内应激条件下红系细胞的产生。此外,毒蕈样乙酰胆碱受体拮抗剂纠正了 MDS 小鼠模型中的贫血、衰老和体内溶血,延长了 MDS 小鼠相对于对照组的存活率。M 受体拮抗剂促进 BFU-Es 扩增的作用是通过转录因子 CREB 的环腺苷酸诱导介导的,其靶基因上调 BFU-E 自我更新的关键调控因子。根据这些数据, 我们提出了一种通过胆碱能介导的 “造血反射” 进行造血祖细胞自我更新的模型,并确定毒蕈样乙酰胆碱受体拮抗剂是与 MDS 、衰老和溶血相关的贫血的潜在疗法。

Acetylcholine

神经 神经递质 临床研究术语
概述  :  

乙酰胆碱(ACh)是最早被确定的一种神经递质。神经系统内以ACh为神经递质的神经元称为胆碱能神经元。ACh自身化学性质很不稳定,在生物组织内释放后又极易被胆碱酯酶水解,这给研究中枢胆碱能神经元的分布及纤维联系带来很大困难。脑内胆碱能神经元主要分为两类:即局部环路细胞(local circuit cell)和投射神经元(projection neuron)。 组成 乙酰胆碱由两部分组成:胆碱(由脂类的分解生成)和乙酰基(醋以及醋酸中含有这种

acetylcholine   英 [,æsɪtaɪl'kəʊliːn; -tɪl-]  美 [,æsətɪl'kolin] 

释    义    n. [有化] 乙酰胆碱

例    句    A better target would be to determine how these [acetylcholine neurons] are learning to staydepressed and work directly with those.一个更好的目标可能是确定这些[乙酰胆碱神经元]是如何学会保持削弱状态并与那些直接共同工作的。

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