FGF signaling in the specification and emergence of hematopoietic stem cells

描述(申请人提供)：造血干细胞(HSCs)是人类骨髓中罕见的细胞，负责造血细胞移植(HCT)的疗效。再生医学的一个主要目标是指导多能前体细胞在体外形成造血干细胞。尽管经过几十年的努力，这一目标仍未实现。因此，需要对脊椎动物胚胎中HSC规范的本地机制有更好的理解才能为这些方法提供信息。最近的研究表明，HSCs起源于血源性内皮细胞，这是一种位于腹主动脉腹壁的特殊内皮细胞，可转分化为HSCs。在这项应用中，我们将利用斑马鱼胚胎的独特优势，更好地了解造血干细胞是如何在基因上指定的。我们的初步发现表明，通过成纤维细胞生长因子(FGFs)的信号在多个阶段调节HSC的发育。成纤维细胞生长因子信号最初似乎需要从后外侧中胚层(PLM)引导HSCs，并随后调节它们从腹主动脉内皮细胞的出现。对相关机制的剖析将有助于更好地洞察指定血液内皮细胞的分子线索，血液内皮细胞是整个脊椎动物门中肝干细胞的诞生地。我们的发现最终将提供以精确、稳健和可重复性的方式从多能前体细胞体外复制人类HSC发育的方法，以满足最终临床实用的要求。

DESCRIPTION (provided by applicant): Hematopoietic stem cells (HSCs) are rare cells within human bone marrow that are responsible for the curative effects of hematopoietic cell transplantation (HCT). A major goal of regenerative medicine is to instruct formation of HSCs in vitro from pluripotent precursors. Despite decades of efforts, this goal has not been achieved. An improved understanding of the native mechanisms of HSC specification in the vertebrate embryo is thus required to inform these approaches. Recent studies have conclusively demonstrated that HSCs arise from hemogenic endothelium, a special population of endothelial cells within the ventral wall of the dorsal aorta that transdifferentiate into HSCs. In this application, we will utilize the unique advantages of the zebrafish embryo to provide a better understanding of how HSCs are specified genetically. Our preliminary findings demonstrate that signaling via fibroblast growth factors (FGFs) regulates HSC development at multiple stages. FGF signaling appears to be required initially to instruct HSCs from posterior lateral mesoderm (PLM), and to subsequently regulate their emergence from ventral aortic endothelium. Dissection of the mechanisms involved will lead to improved insight into the molecular cues that specify hemogenic endothelium, the birthplace of HSCs across vertebrate phyla. Our findings will ultimately provide the means to replicate human HSC development in vitro from pluripotent precursors in a precise, robust, and reproducible manner, requirements for eventual clinical utility.