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Nat Commun:梅杨/冀鹏团队揭示mDia2调控造血干祖细胞骨髓移植关键过程

2020-07-29 酶美 BioArt

研究揭示了Formin蛋白mDia2通过调控直链肌动蛋白束F-actin的合成,促进血清反应因子SRF的活性,调节β2整合素的表达,最终正向调控造血干祖细胞在骨髓移植过程中的转内皮迁移。

造血干祖细胞(HSPCs)是机体内血液细胞的“源泉”,主要存在于骨髓内的干细胞“龛”(niche)中。HSPCs具有迁移(migration)、归巢(homing)和重新植入(engraftment)骨髓的能力,这使得骨髓移植成为临床上治疗众多恶性血液病的常规手段和有效方法。因此,研究造血干祖细胞移植过程中的分子信号网络以期提高造血干祖细胞归巢和植入的效率具有重要意义。

近日,来自美国西北大学Feinberg医学院病理系冀鹏教授团队在Nature Communications杂志发表题为 “Diaphanous-related formin mDia2 regulates beta2 integrins to control hematopoietic stem and progenitor cell engraftment” 的研究论文(梅杨博士为论文第一作者兼共同通讯作者)。该研究揭示了Formin蛋白mDia2通过调控直链肌动蛋白束F-actin的合成,促进血清反应因子SRF的活性,调节β2整合素的表达,最终正向调控造血干祖细胞在骨髓移植过程中的转内皮迁移,确保其在小鼠骨髓中的正常定植和扩增。

研究人员首先对mDia2缺失小鼠的HSPCs进行了功能性分析,发现其在竞争性骨髓移植中定植能力受损;在经骨髓移植后,干细胞的“静息”状态丢失。通过体内成像技术,进一步发现mDia2敲除的HSPCs被阻滞在骨髓内血管内部,无法转内皮迁移进入干细胞“龛”。

随后的分析表明,mDia2缺失导致HSPCs极化能力和粘附能力下降,细胞内的SRF转录活性下调,β2整合素家族基因的表达受到抑制。更近一步的实验证实,β2整合素是转录因子SRF的下游靶基因,在mDia2缺失的HSPCs中重新表达SRF或β2整合素可以“挽救”骨髓移植的缺陷表型。

总之,上述研究揭示了mDia2调控小鼠造血干祖细胞骨髓移植过程的分子机理,解析了mDia2调节HSPCs转内皮迁移植入的过程,开拓了Formin蛋白作为细胞骨架调节因子参与干细胞生物学的新方向。值得注意的是,mDia2蛋白在小鼠的红细胞发育中也扮演重要的角色,如mDia2参与胞质分裂,调控成红细胞的“出核”。这些研究说明mDia2在调节血液系统功能方面有重要作用。

原始出处:

Yang Mei, Xu Han, Yijie Liu , et al.Diaphanous-related formin mDia2 regulates beta2 integrins to control hematopoietic stem and progenitor cell engraftment.Nat Commun. 2020 Jun 23;11(1):3172. doi: 10.1038/s41467-020-16911-4.

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    2020-09-24 liuli5079
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    2021-03-08 医者仁心
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    2020-07-31 俅侠
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