FGF signaling in the specification and emergence of hematopoietic stem cells

描述（申请人提供）：造血干细胞（HSC）是人类骨髓中的稀有细胞，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在体外从多能前体形成造血干细胞。尽管经过数十年的努力，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 规范的天然机制，以便为这些方法提供信息。最近的研究最终证明，造血干细胞起源于造血内皮细胞，造血内皮细胞是背主动脉腹壁内的一个特殊的内皮细胞群，可转分化为造血干细胞。在此应用中，我们将利用斑马鱼胚胎的独特优势来更好地了解 HSC 的遗传特性。我们的初步研究结果表明，通过成纤维细胞生长因子 (FGF) 发出的信号在多个阶段调节 HSC 的发育。 FGF 信号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的出现。对所涉及机制的剖析将有助于更好地了解造血内皮细胞的分子线索，造血内皮细胞是脊椎动物门造血干细胞的诞生地。我们的研究结果最终将提供以精确、稳健和可重复的方式在体外从多能前体复制人类 HSC 发育的方法，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.