由美國賓夕法尼亞大學(xué)醫(yī)學(xué)院細(xì)胞與發(fā)育生物學(xué)教授南希·斯佩克博士領(lǐng)導(dǎo)的一個(gè)研究小組,，在近日完成了大多數(shù)骨髓干細(xì)胞在小鼠胚胎中形成的位置和發(fā)育時(shí)間表,。這項(xiàng)發(fā)表在《自然》雜志上的科學(xué)發(fā)現(xiàn)揭示了造血干細(xì)胞起源的關(guān)鍵步驟,。成年哺乳動(dòng)物骨髓中的造血干細(xì)胞能產(chǎn)生身體的所有血液細(xì)胞類型,，因此解密其來源可能會(huì)幫助研究人員更好地操縱胚胎干細(xì)胞,，以產(chǎn)生新的血液細(xì)胞來進(jìn)行疾病治療,。
先前有研究指出,，造血干細(xì)胞源自血管內(nèi)一種數(shù)量很少的細(xì)胞——內(nèi)皮細(xì)胞,，但研究人員并不了解在早期發(fā)育階段內(nèi)皮細(xì)胞是如何轉(zhuǎn)變?yōu)檠焊杉?xì)胞的,。早在去年9月，斯佩克領(lǐng)導(dǎo)的一個(gè)研究小組就證實(shí)骨髓造血干細(xì)胞源自血管內(nèi)皮細(xì)胞,，并懷疑對(duì)形成血液細(xì)胞很重要的一種蛋白R(shí)unx1的活性是這種轉(zhuǎn)型的關(guān)鍵,。
在新的研究中，研究人員首先滅活了對(duì)小鼠胚胎內(nèi)皮細(xì)胞中的Runx1蛋白進(jìn)行編碼的基因,。在發(fā)育過程中,，一些內(nèi)皮細(xì)胞表達(dá)Runx1，標(biāo)志著像葡萄藤蔓一樣的造血干細(xì)胞簇沿著一些主血管的內(nèi)壁開始產(chǎn)生,。一旦從血管壁脫落,，造血干細(xì)胞就進(jìn)入血液循環(huán)，并流動(dòng)至胎兒的肝臟,；胎兒出生后,，造血干細(xì)胞就轉(zhuǎn)移到骨髓。
通過選擇性地阻斷胚胎發(fā)育過程中血管內(nèi)皮細(xì)胞表達(dá)Runx1的能力,，研究人員就可中止造血干細(xì)胞的產(chǎn)生,，這表明了Runx1對(duì)內(nèi)皮細(xì)胞向造血干細(xì)胞過渡至關(guān)重要。
接著,，斯佩克研究小組關(guān)閉了妊娠11.5天的小鼠胚胎中的Runx1表達(dá),，此時(shí)正是大多數(shù)新生造血干細(xì)胞脫離血管壁并遷移到胎兒肝臟的時(shí)間。研究人員發(fā)現(xiàn),，阻斷Runx1的表達(dá)并不影響造血干細(xì)胞的形成,，這表明從內(nèi)皮細(xì)胞向造血干細(xì)胞的過渡在妊娠第11天時(shí)就已經(jīng)完成,，Runx1在這一關(guān)鍵過渡中起著重要作用。
研究人員還發(fā)現(xiàn),，至少95%%的成人造血干細(xì)胞,，也就是幾乎所有的成人血液均在發(fā)育過程的這個(gè)短暫窗口起源于血管內(nèi)皮細(xì)胞。
斯佩克表示,，該項(xiàng)研究揭示了從胚胎干細(xì)胞向造血干細(xì)胞過渡階段中的一個(gè)非常重要的步驟,，那就是需要內(nèi)皮細(xì)胞作為“中間人”。了解血液細(xì)胞起源的位置和時(shí)間表,，對(duì)今后誘導(dǎo)胚胎干細(xì)胞產(chǎn)生成熟血液細(xì)胞具有指導(dǎo)意義,。（生物谷Bioon.com）
生物谷推薦原始出處：
Nature advance online publication 7 January 2009 | doi:10.1038/nature07619
Runx1 is required for the endothelial to haematopoietic cell transition but not thereafter
Michael J. Chen1,2,4, Tomomasa Yokomizo3, Brandon M. Zeigler1, Elaine Dzierzak3 & Nancy A. Speck1,4
1 Department of Biochemistry,
2 Department of Genetics, Dartmouth Medical School, Hanover, New Hampshire 03755, USA
3 Department of Cell Biology and Genetics, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands
Haematopoietic stem cells (HSCs) are the founder cells of the adult haematopoietic system, and thus knowledge of the molecular program directing their generation during development is important for regenerative haematopoietic strategies. Runx1 is a pivotal transcription factor required for HSC generation in the vascular regions of the mouse conceptus—the aorta, vitelline and umbilical arteries, yolk sac and placenta1, 2. It is thought that HSCs emerge from vascular endothelial cells through the formation of intra-arterial clusters3 and that Runx1 functions during the transition from 'haemogenic endothelium' to HSCs4, 5. Here we show by conditional deletion that Runx1 activity in vascular-endothelial-cadherin-positive endothelial cells is indeed essential for intra-arterial cluster, haematopoietic progenitor and HSC formation in mice. In contrast, Runx1 is not required in cells expressing Vav1, one of the first pan-haematopoietic genes expressed in HSCs. Collectively these data show that Runx1 function is essential in endothelial cells for haematopoietic progenitor and HSC formation from the vasculature, but its requirement ends once or before Vav is expressed.
