女博导Nature破解干细胞分化关键

生物通报道，宾夕法尼亚大学医学院发育干细胞与再生生物学系教授Nancy A. Speck近期在在最新一期的Nature杂志发表干细胞转录研究新成果，该成果揭示了造血干细胞的分化调节因子Runx1的调节机制。

 

Nancy A. Speck早年毕业于Western Maryland College，获得生物和化学学士学位，1982年在NorthWestern University获得免疫学博士学位。现为宾夕法尼亚大学发育干细胞与再生生物学系教授，主要致力于研究造血干细胞的核心结合因子（core binding factors CBFs）和白血病。

 

08年Nancy A. Speck教授研究发现CBFs是自然杀伤细胞发育的必需因子，也是T细胞异化的调控因子，该文章发表在10月的《Blood》杂志上。Nancy A. Speck也曾撰写造血干细胞的研究的综述文章，发表在2008年2月的Nature Immunology上。

 

延续Nancy A. Speck的研究工作，此次她带领的研究小组在造血干细胞转录因子Runx1的研究上取得了新进展，成果公布在Nature杂志上。该研究的意义在于揭示了造血干细胞起源的关键步骤和影响因子。

 

Runx1是该研究中的主要角色，Runx是CBFs的组成部分，是其中的一个亚单位，CBFs有两个亚结构组成，一个是结合DNA的区域，一个是非DNA结合区域，Runx1就是结合DNA的区域，主要分三种，Runx1、Runx2和Runx3。

 

造血干细胞是成年人造血系统中的重要基础细胞，但是造血干细胞是如何发育分化的机制一直没有破解。而Runx1是血管中造血干细胞发育的中枢转录控制因子，有研究认为造血干细胞来自于血管内皮细胞，先生成动脉内的细胞簇，接下来Runx1发挥调控作用，促进细胞簇转化成造血干细胞。

 

在本研究中Nancy A. Speck教授的研究小组将脉管内皮钙粘蛋白阳性的内皮细胞中表达Runx1的基因敲除，结果发现Runx1对动脉内细胞簇的生成具有关键的作用，失去Runx1就无法生成造血干细胞。而另一个有趣的现象是，Runx1的功能能被Vav1弥补，Vav1是首个造血干细胞的pan-Haematopoietic基因表达的蛋白产物。

 

这些研究成果表明，Runx1是控制造血干细胞生成的关键控制因子，不过，对能表达Vav的细胞来说，Runx1却并不是必须的。Runx1是内皮细胞-动脉细胞簇-造血干细胞转型过程中的过度调控因子。

生物通 小茜

原文检索：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

 

Department of Biochemistry,

Department of Genetics, Dartmouth Medical School, Hanover, New Hampshire 03755, USA

Department of Cell Biology and Genetics, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands

Present address: Abramson Family Cancer Research Institute and Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

Correspondence to: Nancy A. Speck1,4 Correspondence and requests for materials should be addressed to N.A.S. (Email: [e-mail]).

【Abstract】

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.