Characterization of Multicellular Niches Supporting Hematopoietic Stem Cells Within Distinct Zones

Dong, R.; Li, H.; He, X. C.; Wang, C.; Perera, A.; Malloy, S.; Russell, J.; Li, W.; Petentler, K.; Mao, X.; Yang, Z.; Epp, M.; Hall, K.; Scott, A.; Smith, S.; Hembree, M.; Wang, Y.; McKinney, S.; Haug, J.; Unruh, J.; Slaughter, B.; Kang, X.; Li, L.

doi:10.1101/2024.06.28.601225

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bioRxiv · 10.1101/2024.06.28.601225

Characterization of Multicellular Niches Supporting Hematopoietic Stem Cells Within Distinct Zones

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Abstract

Previous studies of hematopoietic stem cells (HSCs) primarily focused on single cell-based niche models, yielding fruitful but conflicting findings1-5. Here we report our investigation on the fetal liver (FL) as the primary fetal hematopoietic site using spatial transcriptomics. Our study reveals two distinct niches: the portal-vessel (PV) niche and the sinusoidal niche. The PV niche, composing N-cadherin (N-cad)HiPdgfr+ mesenchymal stromal cells (MSCs), endothelial cells (ECs), and N-cadLoAlbumin+ hepatoblasts, maintains quiescent and multipotential FL-HSCs. Conversely, the sinusoidal niche, comprising ECs, hepatoblasts and hepatocytes, as well as potential macrophages and megakaryocytes, supports proliferative FL-HSCs biased towards myeloid lineages. Unlike prior reports on the role of Cxcl12, with its depletion from vessel-associated stromal cells leading to 80% of HSCs reduction in the adult bone marrow (BM)6,7, depletion of Cxcl12 via Cdh2CreERT (encoding N-cad) induces altered localization of HSCs from the PV to the sinusoidal niches, resulting in an increase of HSC number but with myeloid-bias. Similarly, we discovered that adult BM encompasses two niches within different zones, each composed of multi-cellular components: trabecular bone area (TBA, or metaphysis) supporting deep-quiescent HSCs, and central marrow (CM, or diaphysis) fostering heterogenous proliferative HSCs. This study transforms our understanding of niches by shifting from single cell-based to multicellular components within distinct zones, illuminating the intricate regulation of HSCs tailored to their different cycling states.

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Dong, R., Li, H., He, X. C., Wang, C., Perera, A., Malloy, S., Russell, J., Li, W., Petentler, K., Mao, X., Yang, Z., Epp, M., Hall, K., Scott, A., Smith, S., Hembree, M., Wang, Y., McKinney, S., Haug, J., Unruh, J., Slaughter, B., Kang, X., Li, L.. 2024-07-02. Characterization of Multicellular Niches Supporting Hematopoietic Stem Cells Within Distinct Zones. https://doi.org/10.1101/2024.06.28.601225

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