Stable clonal contribution of lineage-restricted stem cells to human hematopoiesis
Dynamic steady-state lineage contribution of human hematopoietic stem cell (HSC) clones needs to be assessed over time. However, clonal contribution of HSCs has only been investigated at single time points and without assessing the critical erythroid and platelet lineages. Here we screened for somatic mutations in healthy aged individuals, identifying expanded HSC clones accessible for lineage tracing of all major blood cell lineages. In addition to HSC clones with balanced contribution to all lineages, we identified clones with all myeloid lineages but no or few B and T lymphocytes or all myeloid lineages and B cells but no T cells. No other lineage restriction patterns were reproducibly observed. Retrospective phylogenetic inferences uncovered a 'hierarchical' pattern of descendant subclones more lineage biased than their ancestral clone and a more common 'stable' pattern with descendant subclones showing highly concordant lineage contributions with their ancestral clone, despite decades of separation. Prospective lineage tracing confirmed remarkable stability over years of HSC clones with distinct lineage replenishment patterns.
Authors
- Indira Barbosa (ORCID: https://orcid.org/0009-0004-1171-2932)
- Petter Woll (ORCID: https://orcid.org/0000-0002-2340-2526)
- Warren W. Kretzschmar (ORCID: https://orcid.org/0000-0002-2575-0807)
- Eva Hellström‐Lindberg (ORCID: https://orcid.org/0000-0002-7839-3743)
- Margs S. Brennan (ORCID: https://orcid.org/0000-0002-8864-4147)
- Madeleine Lehander (ORCID: https://orcid.org/0009-0005-0114-4502)
- Francesca Grasso
- Stefania Mazzi (ORCID: https://orcid.org/0009-0009-2676-5232)
- Kari Högstrand
- Teresa Mortera‐Blanco (ORCID: https://orcid.org/0000-0002-8399-1430)
- Affaf Aliouat
- Christer Nilsson (ORCID: https://orcid.org/0000-0003-0695-0050)
- Monika Jansson (ORCID: https://orcid.org/0000-0002-9257-0873)
- Tetsuichi Yoshizato (ORCID: https://orcid.org/0000-0003-4283-2983)
- Amy Hillen (ORCID: https://orcid.org/0000-0002-8567-1545)
- Ellen Markljung
- Sten Eirik W. Jacobsen (ORCID: https://orcid.org/0000-0002-1362-3659)
- Edwin Chari
- Axel Winroth (ORCID: https://orcid.org/0009-0002-3314-7781)
- Mikaela Hillberg Widfeldt
- Gunilla Waldin
Institutions
- Karolinska University Hospital (SE)
- Karolinska Institutet (SE)
- MRC Weatherall Institute of Molecular Medicine (GB)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-11-11
- DOI
- https://doi.org/10.1038/s41588-025-02405-w
- Citations
- 1
- Primary Topic
- Hematopoietic Stem Cell Transplantation
- Type
- article
- Field-Weighted Citation Impact
- 1.77
Funders
- Torsten Söderbergs Stiftelse
- Cancerfonden
- Karolinska Institutet
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Astellas Pharma
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Radiumhemmets Forskningsfonder
- Astellas Foundation for Research on Metabolic Disorders
- Science for Life Laboratory
- Medical Research Council
- Center for Innovative Medicine