Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, New York, NY 11724, USA.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Sci Transl Med. 2019 Sep 25;11(511). doi: 10.1126/scitranslmed.aaw3781.
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 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.
成体干细胞和祖细胞具有独特的自我更新能力，针对这一过程代表了一种潜在的治疗机会。早期红系祖细胞，集落形成单位红细胞（BFU-E），具有很大的自我更新潜力，是治疗贫血的关键细胞类型。然而，我们对 BFU-E 自我更新的机制的理解极其有限。在这里，我们发现乙酰胆碱能受体，毒蕈碱型乙酰胆碱受体，M4 型（CHRM4）途径调节 BFU-E 的自我更新，并且 CHRM4 的药理学抑制纠正骨髓增生异常综合征（MDS）、衰老和溶血引起的贫血。CHRM4 的遗传下调或使用选择性拮抗剂 PD102807 对 CHRM4 的药理学抑制促进了 BFU-E 的自我更新，而增加则在体内应激条件下增加了红细胞的产生。此外，毒蕈碱乙酰胆碱受体拮抗剂在体内 MDS、衰老和溶血的小鼠模型中纠正了贫血，使 MDS 小鼠的存活时间相对于对照组延长。毒蕈碱受体拮抗作用对促进 BFU-E 扩增的影响是通过 cAMP 诱导转录因子 CREB 介导的，其靶标上调了 BFU-E 自我更新的关键调节因子。基于这些数据，我们提出了一种通过胆碱能介导的“造血反射”促进造血祖细胞自我更新的模型，并确定毒蕈碱乙酰胆碱受体拮抗剂是治疗与 MDS、衰老和溶血相关的贫血的潜在疗法。
