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| Item Type: | Article |
|---|---|
| Title: | A kinetics-based model of haematopoiesis reveals extrinsic regulation of skewed lineage output from stem cells |
| Creators: |
Rodríguez-Correa, Esther, Grünschläger, Florian, Nizharadze, Tamar, Anstee, Natasha, Al-Sabah, Jude, Kumpost, Vojtech, Sedlmeier, Anastasia  ORCID: https://orcid.org/0009-0002-0418-2131, Li, Congxin, Ball, Melanie, Fotopoulou, Foteini, Jayarajan, Jeyan ORCID: https://orcid.org/0009-0009-6205-143X, Ghezzi, Ian, Knoch, Julia, Druce, Megan, Aurich, Kleo, Büchler-Schäff, Marleen, Lux, Susanne, Hernández-Malmierca, Pablo ORCID: https://orcid.org/0000-0003-4529-384X, Gräsel, Julius, Vonficht, Dominik, López-Osias, Marta, González-Saiz, Elvira ORCID: https://orcid.org/0000-0002-8455-1453, Fernández-Pérez, Daniel, Mathioudaki, Anna ORCID: https://orcid.org/0000-0003-4617-7015, Zaugg, Judith, Rodríguez-Fraticelli, Alejo ORCID: https://orcid.org/0000-0002-4017-8714, Mikut, Ralf, Trumpp, Andreas ORCID: https://orcid.org/0000-0002-6212-3466, Höfer, Thomas ORCID: https://orcid.org/0000-0003-3560-8780, Hübschmann, Daniel ORCID: https://orcid.org/0000-0002-6041-7049, Haas, Simon ORCID: https://orcid.org/0000-0001-9227-2051 and Milsom, Michael D. ORCID: https://orcid.org/0000-0002-3567-254X
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| Abstract: | Haematopoietic stem cells (HSCs) display extensive molecular and functional heterogeneity. However, a cohesive model that explains the relationship and biological relevance of these diverse HSC states remains elusive. Here, by performing single-cell transplantations of over 1,000 highly purified murine long-term HSCs combined with in-depth phenotyping of their clonal progeny, we define kinetics-based reconstitution parameters which aligned HSCs into a single hierarchical trajectory reflective of functional potency. This approach revealed that previously identified lineage biases are actually transitory states along this linear trajectory, not a discrete stable condition. Single-cell secondary transplantations validated hierarchical ordering based on reconstitution kinetics, whereas mathematical modelling combined with experimental modulation of lineage-biased blood production revealed that apparent lineage-biased outputs actually arise from cell-extrinsic feedback regulation and clonal competition between slow- and fast-engrafting clones to fill mature lineages to their compartment size limit. This study reconciles multiple layers of HSC heterogeneity into a unifying framework. |
| Keywords: | Animals, Mice |
| Source: | Nature Cell Biology |
| ISSN: | 1465-7392 |
| Publisher: | Nature Publishing Group |
| Date: | 25 May 2026 |
| Official Publication: | https://doi.org/10.1038/s41556-026-01958-0 |
| PubMed: | View item in PubMed |
| Related to: |
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