Molecular and functional dissection of the zebrafish hematopoietic stem cell niche

项目概要/摘要： 造血干细胞（HSCs）在血液中产生所有终末分化细胞。HSC的能力 重建这些血细胞谱系以维持生命是骨髓移植治疗有效性的基础 用于治疗各种血液疾病，包括白血病、贫血和自身免疫。虽然这是一个 在现有的有效治疗方法中，三分之二需要移植的患者缺乏匹配的供体。 因此，治疗性HSC的替代来源将是该领域的布恩。人多能干细胞 人PSC（hPSC）代表了基于细胞的疗法的潜在来源，包括患者特异性造血干细胞的衍生。 可移植的HSC，这将另外规避免疫排斥和同种异体反应性，两者都是主要的 诊所里的问题。 这项研究的目的是扩展我们对一个新的体节群体的初步观察， 衍生的内皮细胞（SDEC）。值得注意的是，这些细胞只迁移到新生的背主动脉， 作为随后HSC出现的发展利基。SDEC的特性将提供 更深入地了解支配HSC体内发育的线索。我们的基本发现 在这些研究的过程中，将最终告知从hPSC衍生HSC的策略。这项建议 将利用斑马鱼中的谱系追踪方法和hPSC的体外分化方案， 单细胞测序方法，以确定这种要求的分子机制，并提供 一个新的水平的理解后外侧中胚层是如何指示产生HSC。 这些研究的长期目标是更好地了解HSC在胚胎中的发育， 以便将这些信息转化为hPSC。这项研究的顺利完成将对我国的经济发展产生深远的影响。 影响HSC的衍生和扩展，从而将有助于克服目前的障碍， 有效治疗需要骨髓移植治疗的疾病。

Project Summary/Abstract: Hematopoietic stem cells (HSCs) give rise to all terminally differentiated cells in the blood. The ability of HSCs to reconstitute these blood cell lineages for life underlies the efficacy of bone marrow transplantation therapy for treatment of various blood disorders, including leukemias, anemia, and autoimmunity. Although this is an established and effective treatment, two-thirds of patients in need of a transplant lack a matched donor. Therefore, alternative sources of therapeutic HSCs would be a boon to the field. Human pluripotent stem cells (hPSCs) represent a potential source for cell-based therapies, including the derivation of patient-specific transplantable HSCs, which would additionally circumvent immune rejection and alloreactivity, both major issues in the clinic. The goal of the proposed research is to extend our preliminary observations on a novel population of somite- derived endothelial cells (SDECs). Of note, these cells migrate exclusively to the nascent dorsal aorta and act as a developmental niche for the subsequent emergence of HSCs. Characterization of SDECs will provide a deeper understanding of the cues that govern HSC development in vivo. The fundamental discoveries made in the course of these studies will ultimately inform derivation strategies of HSCs from hPSCs. This proposal will leverage lineage tracing methods in zebrafish and in vitro differentiation protocols of hPSCs combined with single-cell sequencing approaches to determine the molecular mechanisms of this requirement, and to provide a new level of understanding of how posterior lateral mesoderm is instructed to generate HSCs. The long-term goal of these studies is to gain a better understanding of how HSCs develop in the embryo in order to translate this information to hPSCs. Successful completion of this research will have a profound impact on HSC derivation and expansion, and thereby will be instrumental in overcoming current obstacles to the effective treatment of diseases requiring bone marrow transplant therapy.