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首页 » 信号转导 » Dev. Cell:裴钢研究组发现凝血酶受体在血液发生和内皮血液转化中的调控作用

Dev. Cell:裴钢研究组发现凝血酶受体在血液发生和内皮血液转化中的调控作用

来源:中科院生化与细胞所 2012-05-02 10:21

4月17日,Developmental Cell发表了中科院上海生科院生化与细胞所裴钢研究组的研究论文“Thrombin Receptor Regulates Hematopoiesis and Endothelial to Hematopoietic Transition"。该论文阐明了F2r-RhoA/ROCK通路在脊椎动物造血发生和EHT中的重要功能,同时证实了F2r信号通路在协调血液发育和血管发育中的作用。

血液发育和血管发育在脊椎动物胚胎发生中是紧密相关的生理过程。人们对血液发育中初始血细胞的产生一直没有清晰的认识。近期研究发现内皮细胞向血液细胞的转化(Endothelial to Hematopoietic Cell Transition, EHT)在造血干细胞产生过程中起着关键作用,但其机制尚不明确。

研究发现,作为G蛋白偶联受体 (G-protein-coupled receptors) 家族成员之一并为血管发育所必需的凝血酶受体(F2r)在胚胎造血过程中发挥关键的负调控作用。研究人员从生物信息学分析着手,发现F2r表达水平在小鼠胚胎干细胞向血液分化和斑马鱼造血发育过程中显著上调;抑制F2r的活性或表达能够显著促进小鼠胚胎干细胞向血液分化和斑马鱼定向造血,而过表达F2r则会导致相反的效应。在进一步的机制研究中确认RhoA/ROCK通路作为F2r的下游信号分子介导了F2r对EHT及造血干细胞产生的负调控作用,从而阐明了F2r-RhoA/ROCK通路在脊椎动物造血发生和EHT中的重要功能,同时证实了F2r信号通路在协调血液发育和血管发育中的作用。此项研究还有可能为提高体外血液分化效率和治疗相关的血液疾病提供新的思路。

该研究项目得到了科技部、国家自然科学基金委、上海市科委和中国科学院的资助。(生物谷Bioon.com)

Thrombin Receptor Regulates Hematopoiesis and Endothelial-to-Hematopoietic Transition

Rui Yue, Haisen Li, Huan Liu, Yuanyuan Li, Bin Wei, Ge Gao, Yi Jin, Tingxi Liu, Liping Wei, Jiulin Du, Gang Pei

Hematopoietic development and vascular development are closely related physiological processes during vertebrate embryogenesis. Recently, endothelial-to-hematopoietic transition (EHT) was demonstrated to be critical for hematopoietic stem and progenitor cell induction, but its underlying regulatory mechanisms remain poorly understood. Here we show that thrombin receptor (F2r), a protease-activated G protein-coupled receptor required for vascular development, functions as a negative regulator during hematopoietic development. F2r is significantly upregulated during hematopoietic differentiation of mouse embryonic stem cells (mESCs) and zebrafish hematopoietic development. Pharmacological or genetic inhibition of F2r promotes hematopoietic differentiation, whereas F2r overexpression shows opposite effects. Further mechanistic studies reveal that F2r-RhoA/ROCK pathway inhibits EHT in vitro and negatively regulates zebrafish EHT and hematopoietic stem cell induction in vivo. Taken together, this study demonstrates a fundamental role of F2r-RhoA/ROCK pathway in vertebrate hematopoiesis and EHT, as well as an important molecular mechanism coordinating hematopoietic and vascular development.

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