1] Australian Regenerative Medicine Institute, Level 1, Building 75, Monash University, Wellington Road, Clayton, Victoria 3800, Australia [2].
1] The Kinghorn Cancer Centre &Cancer Research Program, Garvan Institute of Medical Research, Victoria Street, Darlinghurst, New South Wales 2010, Australia [2] St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Kensington, New South Wales 2052, Australia [3].
Nature. 2014 Aug 21;512(7514):314-8. doi: 10.1038/nature13678. Epub 2014 Aug 13.
Haematopoietic stem cells (HSCs) are self-renewing stem cells capable of replenishing all blood lineages. In all vertebrate embryos that have been studied, definitive HSCs are generated initially within the dorsal aorta (DA) of the embryonic vasculature by a series of poorly understood inductive events. Previous studies have identified that signalling relayed from adjacent somites coordinates HSC induction, but the nature of this signal has remained elusive. Here we reveal that somite specification of HSCs occurs via the deployment of a specific endothelial precursor population, which arises within a sub-compartment of the zebrafish somite that we have defined as the endotome. Endothelial cells of the endotome are specified within the nascent somite by the activity of the homeobox gene meox1. Specified endotomal cells consequently migrate and colonize the DA, where they induce HSC formation through the deployment of chemokine signalling activated in these cells during endotome formation. Loss of meox1 activity expands the endotome at the expense of a second somitic cell type, the muscle precursors of the dermomyotomal equivalent in zebrafish, the external cell layer. The resulting increase in endotome-derived cells that migrate to colonize the DA generates a dramatic increase in chemokine-dependent HSC induction. This study reveals the molecular basis for a novel somite lineage restriction mechanism and defines a new paradigm in induction of definitive HSCs.
造血干细胞（HSCs）是自我更新的干细胞，能够补充所有血液谱系。在所有已研究的脊椎动物胚胎中，最初通过一系列尚未完全理解的诱导事件，在胚胎脉管系统的背主动脉（DA）中产生确定性 HSCs。先前的研究已经确定，来自相邻体节的信号转导协调 HSC 诱导，但该信号的性质仍然难以捉摸。在这里，我们揭示了 HSCs 的体节特异性是通过特定的内皮前体细胞群的部署来实现的，该细胞群起源于我们定义为内胚层的斑马鱼体节的一个亚区。内胚层的内皮细胞通过活性基因 meox1 在新生体节中被指定。指定的内胚层细胞随后迁移并殖民 DA，在那里它们通过在形成内胚层过程中激活这些细胞中的趋化因子信号诱导 HSC 形成。meox1 活性的丧失以牺牲第二种体节细胞类型为代价扩展内胚层，即斑马鱼中的真皮肌节同源物的肌肉前体，即外细胞层。迁移到 DA 殖民的内胚层衍生细胞的增加导致趋化因子依赖性 HSC 诱导的急剧增加。这项研究揭示了一种新的体节谱系限制机制的分子基础，并定义了确定性 HSCs 诱导的新范例。
