Infantile (fetal and neonatal) megakaryocytes (Mks) have a distinct phenotype consisting of hyperproliferation, limited morphogenesis, and low platelet production capacity. These properties contribute to clinical problems that include thrombocytopenia in neonates, delayed platelet engraftment in recipients of cord blood stem cell transplants, and inefficient ex vivo platelet production from pluripotent stem cell–derived Mks. The infantile phenotype results from deficiency of the actin-regulated coactivator, MKL1, which programs cytoskeletal changes driving morphogenesis. As a strategy to complement this molecular defect, we screened pathways with the potential to affect MKL1 function and found that DYRK1A inhibition dramatically enhanced Mk morphogenesis in vitro and in vivo. Dyrk1 inhibitors rescued enlargement, polyploidization, and thrombopoiesis in human neonatal Mks. Mks derived from induced pluripotent stem cells responded in a similar manner. Progenitors undergoing Dyrk1 inhibition demonstrated filamentous actin assembly, MKL1 nuclear translocation, and modulation of MKL1 target genes. Loss-of-function studies confirmed MKL1 involvement in this morphogenetic pathway. Expression of Ablim2, a stabilizer of filamentous actin, increased with Dyrk1 inhibition, and Ablim2 knockdown abrogated the actin, MKL1, and morphogenetic responses to Dyrk1 inhibition. These results delineate a pharmacologically tractable morphogenetic pathway whose manipulation may alleviate clinical problems associated with the limited thrombopoietic capacity of infantile Mks.

中文翻译：

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解除 DYRK1A 对 MKL1 的抑制赋予人类婴儿巨核细胞类似成人的表型


婴儿（胎儿和新生儿）巨核细胞 (Mks) 具有独特的表型，包括过度增殖、有限的形态发生和低血小板生成能力。这些特性导致临床问题，包括新生儿血小板减少症、脐带血干细胞移植受者血小板植入延迟以及多能干细胞衍生 Mks 体外血小板生成效率低下。婴儿表型是由于肌动蛋白调节的共激活因子 MKL1 缺乏所致，MKL1 负责编程驱动形态发生的细胞骨架变化。作为弥补这一分子缺陷的策略，我们筛选了可能影响 MKL1 功能的途径，发现 DYRK1A 抑制可显着增强体外和体内 Mk 形态发生。 Dyrk1 抑制剂可挽救人类新生儿 Mks 的增大、多倍化和血小板生成。源自诱导多能干细胞的 Mks 以类似的方式做出反应。经历 Dyrk1 抑制的祖细胞表现出丝状肌动蛋白组装、MKL1 核转位和 MKL1 靶基因的调节。功能丧失研究证实 MKL1 参与了这一形态发生途径。 Ablim2（一种丝状肌动蛋白的稳定剂）的表达随着 Dyrk1 的抑制而增加，而 Ablim2 的敲除消除了肌动蛋白、MKL1 和对 Dyrk1 抑制的形态发生反应。这些结果描绘了一种药理学上易于处理的形态发生途径，其操作可以缓解与婴儿 Mks 有限的血小板生成能力相关的临床问题。