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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 Name: | Rodríguez-Correa, Esther, Grünschläger, Florian, Nizharadze, Tamar, Anstee, Natasha, Al-Sabah, Jude, Kumpost, Vojtech, Sedlmeier, Anastasia, Li, Congxin, Ball, Melanie, Fotopoulou, Foteini, Jayarajan, Jeyan, Ghezzi, Ian, Knoch, Julia, Druce, Megan, Aurich, Kleo, Büchler-Schäff, Marleen, Lux, Susanne, Hernández-Malmierca, Pablo, Gräsel, Julius, Vonficht, Dominik, López-Osias, Marta, González-Saiz, Elvira, Fernández-Pérez, Daniel, Mathioudaki, Anna, Zaugg, Judith, Rodríguez-Fraticelli, Alejo, Mikut, Ralf, Trumpp, Andreas, Höfer, Thomas, Hübschmann, Daniel, Haas, Simon and Milsom, Michael D. |
| 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 |
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