Continuous map of early hematopoietic stem cell differentiation across human lifetime

Hana Komic, Tessa Schmachtel, Catia Simoes, Marius Külp, Weijia Yu, Adrien Jolly, Malin S. Nilsson, Carmen Gonzalez, Felipe Prosper, Halvard Bonig, Bruno Paiva, Fredrik B. Thorén and Michael A. Rieger ()
Additional contact information
Hana Komic: University of Gothenburg
Tessa Schmachtel: Goethe University Frankfurt
Catia Simoes: CIBER-ONC number CB16/12/00369 and CB16/12/00489
Marius Külp: Goethe University Frankfurt
Weijia Yu: Goethe University Frankfurt
Adrien Jolly: Goethe University Frankfurt
Malin S. Nilsson: University of Gothenburg
Carmen Gonzalez: CIBER-ONC number CB16/12/00369 and CB16/12/00489
Felipe Prosper: CIBER-ONC number CB16/12/00369 and CB16/12/00489
Halvard Bonig: Goethe University Frankfurt
Bruno Paiva: CIBER-ONC number CB16/12/00369 and CB16/12/00489
Fredrik B. Thorén: University of Gothenburg
Michael A. Rieger: Goethe University Frankfurt

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-57096-y

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