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<p>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.</p>

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A kinetics-based model of haematopoiesis reveals extrinsic regulation of skewed lineage output from stem cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月25日

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

摘要

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.