FGF signaling in the specification and emergence of hematopoietic stem cells

描述（由申请人提供）：造血干细胞（HSC）是人骨髓中的稀有细胞，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从多能前体体外形成HSC。尽管经过几十年的努力，这一目标仍未实现。因此，需要更好地了解脊椎动物胚胎中HSC特化的天然机制，以告知这些方法。最近的研究已经最终证明，HSC来自生血内皮细胞，生血内皮细胞是背主动脉腹侧壁内的内皮细胞的特殊群体，其转分化为HSC。在本申请中，我们将利用斑马鱼胚胎的独特优势，以更好地了解HSC是如何遗传特异性的。我们的初步研究结果表明，通过成纤维细胞生长因子（FGF）的信号调节HSC的发展在多个阶段。FGF信号传导似乎最初需要从后外侧中胚层（PLM）指导HSC，并随后调节它们从腹主动脉内皮出现。解剖所涉及的机制将导致更好地了解分子线索，指定造血内皮细胞，整个脊椎动物门的HSC的发源地。我们的研究结果将最终提供一种方法，以精确、稳健和可重复的方式从多能前体体外复制人HSC发育，这是最终临床应用的要求。

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.