Generation of Hematopoietic Stem and Progenitor Cells from Multiple Source-Derived Endothelial Cells

造血干细胞（hsc）是一个人一生中整个血液系统的中心组织者。最近的研究结果有力地支持了造血干细胞是由妊娠中期小鼠胚胎中的造血内皮细胞（HECs）通过一个称为内皮向造血转化（EHT）的过程形成的概念。因此，更深入地了解胚胎发育过程中控制EHT和造血干细胞随后成熟的潜在过程可能是从非造血细胞来源（如诱导多能干细胞（iPS-）细胞）高效生成造血干细胞的关键先决条件。通过消除与同种异体干细胞移植相关的危及生命的移植物抗宿主病的风险，ipsc衍生的造血干细胞可能在未来为患者量身定制的基于自体造血干细胞的细胞疗法中具有很大的前景。这个中德联合项目的目标是基于对胚胎、出生后和多能干细胞（PSC）来源的内皮细胞的个体发生调控机制的见解，生成造血干细胞。在协调的一步一步的方法中，我们将首先从胚胎和分化的PSCs中纯化造血内皮亚群，通过转录组分析确定它们的分子身份，并确定它们的发育潜能。由于已知外源性小生境细胞在不同解剖部位和不同发育阶段控制HSC的发育，我们将研究一组基质细胞的适用性，以支持小鼠和人类eht后/前HSC的完全成熟。在体外和体内系统中发现的特异性和一致表达的基因，包括最近发现的两个候选基因，将被询问它们在内皮细胞和造血细胞中通过异位表达和组织特异性敲除在造血干细胞的出现、成熟和扩增中的作用。

Hematopoietic stem cells (HSCs) are the central organizers of the entire blood system throughout the lifetime of an individual. Recent findings strongly support the concept that HSCs are formed from hemogenic endothelial cells (HECs) in mid-gestation mouse embryos by a process termed endothelial-to-hematopoietic transition (EHT). Therefore, a deeper understanding of the underlying processes controlling EHT and the subsequent maturation of HSCs during embryonic development presumably is a key prerequisite for the efficient generation of HSCs from non-hematopoietic cell sources, such as induced pluripotent stem (iPS-) cells. iPSC-derived HSCs may hold great promise for patient-tailored, autologous HSC-based cell therapies in future by eliminating the risk of a life-threatening graft-versus-host disease associated with allogeneic stem cell transplantation.The aim of this joint Chinese-German project is to generate HSCs from endothelial cells of embryonic, postnatal and pluripotent stem cell (PSC) - derived sources, based on insights into the regulatory mechanisms of their ontogeny. In a coordinated step-by-step approach, we will first purify hemogenic endothelium subpopulations both from embryos and differentiating PSCs, define their molecular identity by transcriptome analysis and determine their developmental potencies. Because extrinsic niche cells are known to control HSC development at different anatomical sites and during different developmental stages, we will investigate the suitability of a set of stroma cells to support a full maturation of the post-EHT/pre-HSCs of mice and humans. Genes found to be specifically and concordantly expressed both in the in vitro and in vivo systems, including two recently identified candidates, will be interrogated for their role in the emergence, maturation and expansion of HSCs by ectopic expression and tissue-specific knockouts in endothelial and hematopoietic cells.