Tissue-specific and stress-related heterogeneity in the adult human haematopoietic stem cell pool

成人造血干细胞库中的组织特异性和应激相关异质性

• 批准号: 411695144
• 负责人: Dr. Nicole Mende
• 金额: --
• 依托单位: Wellcome - MRC Cambridge Stem Cell Institute
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/411695144?language=en
• 关键词: Tissue; specific; stress; related; heterogeneity

Haematopoietic stem cells (HSCs) generate all blood cells in our body and their transplantation is often the only therapeutic alternative to treat blood disorders. Despite human HSCs having been used for clinical transplantation for more than 30 years, knowledge of their biology is still very poor. Animal models have shown that the HSC pool is not homogeneous and that there are different HSC subsets with distinct functional behaviours and molecular make-ups. It is also thought that regulation of these distinct HSC subsets is key to maintain blood formation over a lifetime. However, very little is known about HSC subsets in humans and how they contribute to steady-state blood production, stress-response or disease.Here, I aim to comprehensively characterize the single-cell composition of the human HSC pool within the three main adult haematopoietic sites (bone marrow, spleen, peripheral blood) at steady state and under stress conditions. Combining state-of-the-art functional assays and single-cell RNA-Sequencing, I will first define the differentiation potential and the transcriptional programmes of human HSCs at steady state, generating an integrative map of the phenotypic, functional and molecular HSC landscape across healthy adult tissues. The functional properties of novel HSC subsets identified by this atlas will be validated in vitro and by xenotransplantation in vivo. Furthermore, tissue-specific and subset-specific transcriptional networks as well as shared HSC programmes will be derived bioinformatically, providing a fundamental resource for the stem cell and haematology field. Second, I will study how stress alters subset composition of the human HSC pool. Preliminary data identified a novel phenotypic HSC population only present in the blood of individuals that frequently donate platelets. Using similar approaches as above, I will determine its properties as well as the molecular signals mediating its appearance and its biological regulation. Collectively, this project will significantly advance our mechanistic understanding of adult human HSC biology at steady state and under stress, thereby opening new avenues for regenerative medicine and strategies to treat blood disorders.

造血干细胞(HSCs)产生我们体内的所有血细胞，它们的移植通常是治疗血液疾病的唯一选择。尽管人类造血干细胞用于临床移植已有30多年的历史，但人们对其生物学方面的了解仍然很少。动物模型表明，HSC池并不是同质的，存在不同的HSC亚群，具有不同的功能行为和分子组成。也有人认为，调节这些不同的HSC亚群是终生维持血液形成的关键。然而，关于人类的HSC亚群以及它们如何在稳定状态下产生血液、应激反应或疾病方面所知甚少。在这里，我的目的是全面地表征稳定状态和应激条件下三个主要成人造血部位(骨髓、脾、外周血)内人类HSC池的单细胞组成。结合最先进的功能分析和单细胞RNA测序，我将首先定义稳定状态下人类HSC的分化潜力和转录程序，生成健康成人组织中HSC表型、功能和分子景观的综合图谱。本图谱确定的新的HSC亚群的功能特性将在体外和体内通过异种移植进行验证。此外，特定于组织和特定亚组的转录网络以及共享的HSC程序将以生物信息的方式产生，为干细胞和血液学领域提供基本的资源。其次，我将研究压力如何改变人类HSC池的子集组成。初步数据证实，一种新的表型HSC群体只存在于经常捐献血小板的人的血液中。使用与上述类似的方法，我将确定它的性质以及调节其外观和生物调节的分子信号。总而言之，该项目将极大地促进我们对处于稳定状态和压力下的成人人类HSC生物学的机械理解，从而为再生医学和治疗血液疾病的策略开辟新的途径。