Cellular and molecular components of a functional niche for human and mouse hematopoietic stem cells.

人类和小鼠造血干细胞功能生态位的细胞和分子成分。

• 批准号: 245329438
• 负责人: Professorin Dr. Claudia Waskow
• 金额: --
• 依托单位: Forschungsgruppe Regeneration in der Hämatopoese
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/245329438?language=en
• 关键词: Cellular; molecular; components; functional; niche

The aim of this research proposal is the definition and characterization of niche cells and their molecular factors controlling the function of blood-forming human and murine stem cells in the bone marrow. To this end, based on gene expression data, we established an interactome between niche cells and hematopoietic stem cells (HSCs). In the next funding period we will determine the role of candidate genes on HSC function in vitro and in vivo using CRISPR-Cas9 technology. We could show that the transplantation of hematopoietic cells accelerates the recovery of niche cells from ionizing irradiation and we will analyze the cellular and molecular mechanism of that support in vivo. Finally, we generated a mouse strain that supports the maintenance and function of human HSCs in vivo and we could show in the last funding period that murine niche cells respond to donor human HSCs by expansion and alterations in their gene expression profile. Taking advantage of this unique mouse strain, we will determine molecular regulators that are the basis for cross-species compatibility of the HSC niche in vivo. Together, the results of our project will contribute to an improved understanding of regulatory circuits important for the function and potentially the modulation of HSC biology in vivo. Such knowledge will be pivotal to solve acute problems in transplantation biology such as paucity of histocompatible donor cells and graft rejection.

这项研究计划的目的是定义和表征利基细胞及其控制骨髓中造血人和小鼠干细胞功能的分子因素。为此，在基因表达数据的基础上，我们建立了细胞与造血干细胞(HSCs)之间的相互作用组。在下一个资助阶段，我们将利用CRISPR-Cas9技术确定候选基因在体外和体内对HSC功能的作用。我们可以证明，造血细胞移植加速了壁龛细胞从电离辐射中恢复，我们将在体内分析这种支持的细胞和分子机制。最后，我们创造了一种小鼠品系，它支持人类造血干细胞在体内的维持和功能，我们可以在上一个资助期展示，小鼠的利基细胞通过扩增和改变其基因表达谱来响应捐赠者的人类造血干细胞。利用这一独特的小鼠品系，我们将确定作为体内HSC生态位跨物种兼容性基础的分子调节因子。总之，我们项目的结果将有助于更好地理解调节电路，这些调节电路对体内HSC生物学的功能和潜在的调节非常重要。这些知识将是解决移植生物学中的尖锐问题的关键，例如组织相容供体细胞的缺乏和移植排斥。