Continuous map of early hematopoietic stem cell differentiation across human lifetime
Uncovering early gene network changes of human hematopoietic stem cells (HSCs) leading to differentiation induction is of utmost importance for therapeutic manipulation. We employed single cell proteo-transcriptomic sequencing to FACS-enriched bone marrow hematopoietic stem and progenitor cells (HSPCs) from 15 healthy donors. Pseudotime analysis reveals four major differentiation trajectories, which remain consistent upon aging, with an early branching point into megakaryocyte-erythroid progenitors. However, young donors suggest a more productive differentiation from HSPCs to committed progenitors of all lineages. tradeSeq analysis depicts continuous changes in gene expression of HSPC-related genes (DLK1, ADGRG6), and provides a roadmap of gene expression at the earliest branching points. We identify CD273/PD-L2 to be highly expressed in a subfraction of immature multipotent HSPCs with enhanced quiescence. Functional experiments confirm the immune-modulatory function of CD273/PD-L2 on HSPCs in regulating T-cell activation and cytokine release. Here, we present a molecular map of early HSPC differentiation across human life.
Authors
- Weijia Yu (ORCID: https://orcid.org/0000-0001-8471-3048)
- Malin S. Nilsson (ORCID: https://orcid.org/0000-0002-0981-2617)
- Hana Komic (ORCID: https://orcid.org/0000-0001-5209-393X)
- Felipe Prósper (ORCID: https://orcid.org/0000-0001-6115-8790)
- Marius Külp (ORCID: https://orcid.org/0000-0002-6594-8412)
- Michael A. Rieger (ORCID: https://orcid.org/0000-0002-4158-5872)
- Adrien Jolly (ORCID: https://orcid.org/0000-0002-2609-5621)
- Fredrik B. Thorén (ORCID: https://orcid.org/0000-0003-2167-7451)
- Bruno Paiva (ORCID: https://orcid.org/0000-0003-1977-3815)
- Catia Simoes (ORCID: https://orcid.org/0000-0002-5713-8428)
- Halvard Bönig (ORCID: https://orcid.org/0000-0003-0088-2675)
- Tessa Schmachtel
- Carmen González (ORCID: https://orcid.org/0009-0001-3074-9229)
Institutions
- Goethe University Frankfurt (DE)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- Sahlgrenska University Hospital (SE)
- Clinica Universidad de Navarra (ES)
- Cardio-Pulmonary Institute (DE)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Frankfurt Cancer Institute (DE)
- University of Gothenburg (SE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-07
- DOI
- https://doi.org/10.1038/s41467-025-57096-y
- Citations
- 14
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 11.28
Funders
- Deutsche Forschungsgemeinschaft
- Hessisches Ministerium für Wissenschaft und Kunst
- José Carreras Leukämie-Stiftung