4月17日,，Developmental Cell發(fā)表了中科院上海生科院生化與細(xì)胞所裴鋼研究組的研究論文“Thrombin Receptor Regulates Hematopoiesis and Endothelial to Hematopoietic Transition",。該論文闡明了F2r-RhoA/ROCK通路在脊椎動(dòng)物造血發(fā)生和EHT中的重要功能，同時(shí)證實(shí)了F2r信號(hào)通路在協(xié)調(diào)血液發(fā)育和血管發(fā)育中的作用,。
血液發(fā)育和血管發(fā)育在脊椎動(dòng)物胚胎發(fā)生中是緊密相關(guān)的生理過程,。人們對(duì)血液發(fā)育中初始血細(xì)胞的產(chǎn)生一直沒有清晰的認(rèn)識(shí)。近期研究發(fā)現(xiàn)內(nèi)皮細(xì)胞向血液細(xì)胞的轉(zhuǎn)化(Endothelial to Hematopoietic Cell Transition, EHT)在造血干細(xì)胞產(chǎn)生過程中起著關(guān)鍵作用,，但其機(jī)制尚不明確,。
研究發(fā)現(xiàn)，作為G蛋白偶聯(lián)受體 (G-protein-coupled receptors) 家族成員之一并為血管發(fā)育所必需的凝血酶受體(F2r)在胚胎造血過程中發(fā)揮關(guān)鍵的負(fù)調(diào)控作用,。研究人員從生物信息學(xué)分析著手,，發(fā)現(xiàn)F2r表達(dá)水平在小鼠胚胎干細(xì)胞向血液分化和斑馬魚造血發(fā)育過程中顯著上調(diào),；抑制F2r的活性或表達(dá)能夠顯著促進(jìn)小鼠胚胎干細(xì)胞向血液分化和斑馬魚定向造血，而過表達(dá)F2r則會(huì)導(dǎo)致相反的效應(yīng),。在進(jìn)一步的機(jī)制研究中確認(rèn)RhoA/ROCK通路作為F2r的下游信號(hào)分子介導(dǎo)了F2r對(duì)EHT及造血干細(xì)胞產(chǎn)生的負(fù)調(diào)控作用,，從而闡明了F2r-RhoA/ROCK通路在脊椎動(dòng)物造血發(fā)生和EHT中的重要功能，同時(shí)證實(shí)了F2r信號(hào)通路在協(xié)調(diào)血液發(fā)育和血管發(fā)育中的作用,。此項(xiàng)研究還有可能為提高體外血液分化效率和治療相關(guān)的血液疾病提供新的思路,。
該研究項(xiàng)目得到了科技部、國家自然科學(xué)基金委,、上海市科委和中國科學(xué)院的資助,。（生物谷Bioon.com）
doi:10.1016/j.devcel.2012.01.025
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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.
