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

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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.