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

从多种来源的内皮细胞生成造血干细胞和祖细胞

• 批准号: 266532227
• 负责人: Professor Dr. Hannes Klump, Ph.D.
• 金额: --
• 依托单位: Laboratory of Oncology
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/266532227?language=en
• 关键词: Generation; Hematopoietic; Stem; Progenitor; Cells

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.

造血干细胞（HSC）是个体一生中整个血液系统的中心组织者。最近的研究结果强烈支持这一概念，即造血干细胞是由生血内皮细胞（HEC）在妊娠中期的小鼠胚胎通过一个过程称为内皮细胞造血转换（EHT）。因此，更深入地了解胚胎发育过程中控制EHT和随后HSC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）有效生成HSC的关键先决条件。iPSC衍生的HSC可能会在未来为患者量身定制，基于自体HSC的细胞疗法带来巨大的希望，因为它消除了与异基因干细胞移植相关的危及生命的移植物抗宿主病的风险。这个中德联合项目的目的是从胚胎，出生后和多能干细胞（PSC）来源的内皮细胞中产生HSC，基于对个体发育调节机制的深入了解。在一个协调的一步一步的方法中，我们将首先从胚胎和分化的PSC中纯化生血内皮细胞亚群，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发育，因此我们将研究一组基质细胞是否适合支持小鼠和人类EHT后/前HSC的完全成熟。发现在体外和体内系统中特异性和一致性表达的基因，包括两个最近鉴定的候选基因，将通过在内皮细胞和造血细胞中的异位表达和组织特异性敲除来询问它们在HSC的出现、成熟和扩增中的作用。