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

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.