Tyrosyl-tRNA synthetase stimulates thrombopoietin-independent hematopoiesis accelerating recovery from thrombocytopenia.
Tyrosyl-tRNA synthetase stimulates thrombopoietin-independent hematopoiesis accelerating recovery from thrombocytopenia.
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酪氨酰-tRNA 合成酶刺激血小板生成素非依赖性造血，加速血小板减少症的恢复。
DOI：
10.1073/pnas.1807000115
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发表时间：
2018-08-28
影响因子：
11.1
通讯作者：
Schimmel P
中科院分区：
文献类型：
--
作者：
Kanaji T;Vo MN;Kanaji S;Zarpellon A;Shapiro R;Morodomi Y;Yuzuriha A;Eto K;Belani R;Do MH;Yang XL;Ruggeri ZM;Schimmel P
氨基酰- trna合成酶（aaRSs）在细胞质中蛋白质合成的第一步催化trna的氨基酰化。然而，在高等真核生物中，它们获得了翻译之外的额外功能。在本研究中，我们发现一种激活形式的酪氨酸- trna合成酶（YRSACT）在体外和体内都能促进巨核生成和血小板产生。这些发现在外周血CD34+造血干细胞和人诱导多能干细胞分化的人巨核细胞中得到证实。YRSACT的活性独立于血小板生成素（TPO），从TPO信号缺陷患者的iPS细胞衍生的造血干细胞中扩增出巨核细胞证明了这一点。这些发现证明了aaRS以前未被认识到的功能，这可能对治疗干预有影响。血细胞形成背后的新机制不断被发现，血液疾病的治疗方法引起了极大的兴趣。在这里，我们报告了蛋白质合成中的一种酶，以翻译之外的细胞活性而闻名，是一种诱导巨核细胞偏向性造血的因素，最有可能在应激条件下发生。我们展示了一种激活形式的酪氨酸- trna合成酶（YRSACT），通过合理设计的诱变或选择性剪接制备，诱导以前未被识别的高倍性Sca-1+巨核细胞群体的扩增，能够加速血小板耗尽后的补充。此外，YRSACT靶向单核细胞诱导分泌交易细胞因子，增强巨核细胞扩张，刺激toll样受体/MyD88通路。通过YRSACT补充血小板不依赖于血小板生成素（TPO），从诱导多能干细胞衍生的造血干细胞中扩增出的巨核细胞证明了TPO信号缺乏的患者。我们认为，YRSACT诱导的巨核细胞偏向性造血为治疗血小板减少症、提高用于输血的血小板浓缩物的细胞培养产量以及造血干细胞移植的桥接治疗提供了新的途径。
Aminoacyl-tRNA synthetases (aaRSs) catalyze aminoacylation of tRNAs in the first step of protein synthesis in the cytoplasm. However, in higher eukaryotes, they acquired additional functions beyond translation. In the present study, we show that an activated form of tyrosyl-tRNA synthetase (YRSACT) functions to enhance megakaryopoiesis and platelet production in vitro and in vivo. These findings were confirmed with human megakaryocytes differentiated from peripheral blood CD34+ hematopoietic stem cells and with human induced pluripotent stem (iPS) cells. The activity of YRSACT is independent of thrombopoietin (TPO), as evidenced by expansion of the megakaryocytes from iPS cell-derived hematopoietic stem cells from a patient deficient in TPO signaling. These findings demonstrate a previously unrecognized function of an aaRS which may have implications for therapeutic interventions. New mechanisms behind blood cell formation continue to be uncovered, with therapeutic approaches for hematological diseases being of great interest. Here we report an enzyme in protein synthesis, known for cell-based activities beyond translation, is a factor inducing megakaryocyte-biased hematopoiesis, most likely under stress conditions. We show an activated form of tyrosyl-tRNA synthetase (YRSACT), prepared either by rationally designed mutagenesis or alternative splicing, induces expansion of a previously unrecognized high-ploidy Sca-1+ megakaryocyte population capable of accelerating platelet replenishment after depletion. Moreover, YRSACT targets monocytic cells to induce secretion of transacting cytokines that enhance megakaryocyte expansion stimulating the Toll-like receptor/MyD88 pathway. Platelet replenishment by YRSACT is independent of thrombopoietin (TPO), as evidenced by expansion of the megakaryocytes from induced pluripotent stem cell-derived hematopoietic stem cells from a patient deficient in TPO signaling. We suggest megakaryocyte-biased hematopoiesis induced by YRSACT offers new approaches for treating thrombocytopenia, boosting yields from cell-culture production of platelet concentrates for transfusion, and bridging therapy for hematopoietic stem cell transplantation.
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影响因子：
64.8
作者：
He W;Bai G;Zhou H;Wei N;White NM;Lauer J;Liu H;Shi Y;Dumitru CD;Lettieri K;Shubayev V;Jordanova A;Guergueltcheva V;Griffin PR;Burgess RW;Pfaff SL;Yang XL
通讯作者：
Yang XL
影响因子：
14.8
作者：
Guo, Min;Schimmel, Paul
通讯作者：
Schimmel, Paul
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
64.8
作者：
Arif A;Terenzi F;Potdar AA;Jia J;Sacks J;China A;Halawani D;Vasu K;Li X;Brown JM;Chen J;Kozma SC;Thomas G;Fox PL
通讯作者：
Fox PL
影响因子：
3.8
作者：
Beck, G;Habicht, GS
通讯作者：
Habicht, GS