PhD Student Josep Carreras Leukaemia Research Institute, Spain
Abstract: Haematopoietic stem cells (HSCs) are multipotent cells characterised by self-renewal, multilineage differentiation and engraftment ability. Human HSCs that first emerge in the aorta-gonad-mesonephros, transition to foetal liver (FL) where they undergo expansion and functional maturation. From mid second trimester onwards, HSCs start relocating to bone marrow (BM), the niche where they will reside throughout life to support haematopoiesis. However, the mechanisms underlying the HSCs transition from FL to BM in humans are poorly understood.
To understand the factors driving the relocation of HSCs to BM and their molecular implications, we investigated the dynamic changes in FL and BM HSCs derived from the same embryos at 19 weeks post conception, using a single-nucleus multiome assay, which simultaneously profiles gene expression and chromatin accessibility. We analysed the cell-intrinsic differences, comparing highly-purified HSCs isolated from both niches, and the cell-extrinsic cues of FL and BM environments, which contain the niche cells providing essential signals to HSCs.
Transcriptome data shows that, while the expression levels of genes related to HSC maturity is comparable, the expression of HSC signature genes such as RUNX1, MLLT3, and HLF is increased in BM HSCs. In addition, we observe downregulation of the translational machinery in BM HSCs, suggesting the progression towards quiescence. Upregulation of genes linked to the granulocytic lineage points to an expansion of the multilineage potential of the HSCs in the bone marrow. Overall, chromatin accessibility exhibits minor changes at this stage. Aside from the intrinsic HSC changes, we also evidence various differences in ligand-receptor signalling from the niche to HSCs: cytokines and chemokines such as KITL and CXCL12, feature different expression levels and connectivity between FL and BM stromal cell populations, supporting an evolving role of the niche signalling within same-age HSCs. These findings contribute to an advanced understanding of the development of HSCs in humans, and highlight the need for suitable niche-derived support for functional HSC generation in vitro.
