FGF signaling in the specification and emergence of hematopoietic stem cells

描述（由申请人提供）：造血干细胞（Hematopoietic stem cells, hsc）是人类骨髓中的稀有细胞，负责造血细胞移植（Hematopoietic cell transplantation， HCT）的疗效。再生医学的一个主要目标是指导多能性前体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规范的原生机制有更好的了解，从而为这些方法提供信息。最近的研究明确表明造血干细胞起源于造血内皮，这是一种特殊的内皮细胞群，位于背主动脉腹壁上，可转分化为造血干细胞。在这个应用中，我们将利用斑马鱼胚胎的独特优势来更好地理解造血干细胞是如何在基因上被指定的。我们的初步研究结果表明，通过成纤维细胞生长因子（FGFs）的信号传导在多个阶段调节HSC的发育。FGF信号最初似乎需要从后外侧中胚层（PLM）引导hsc，随后调节它们从腹主动脉内皮的出现。解剖所涉及的机制将导致更好地了解指定造血内皮的分子线索，造血干细胞的发源地跨越脊椎动物门。我们的研究结果最终将提供从多能性前体在体外以精确、稳健和可重复的方式复制人类HSC发育的方法，以满足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.