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| Item Type: | Preprint |
|---|---|
| Title: | A kinetics-based model of hematopoiesis reveals extrinsic regulation of skewed lineage output from stem cells |
| Creators Name: | Rodriguez-Correa, E., Gruenschlaeger, F., Nizharadze, T., Anstee, N., Al-Sabah, J., Kumpost, V., Sedlmeier, A., Li, C., Ball, M., Fotopoulou, F., Jayarajan, J., Ghezzi, I., Knoch, J., Druce, M., Aurich, T., Buechler-Schaeff, M., Lux, S., Hernandez-Malmierca, P., Graesel, J., Vonficht, D., Mathioudaki, A., Zaugg, J.B., Mikut, R., Trumpp, A., Hoefer, T., Huebschmann, D., Haas, S. and Milsom, M.D. |
| Abstract: | Residing at the top of the hematopoietic hierarchy, long-term hematopoietic stem cells (HSCs) are capable of self-renewal and sustained blood cell regeneration. Over the past decades, single-cell and clonal analyses have revealed substantial functional and molecular heterogeneity within this compartment, challenging the notion that self-renewal is inherently tied to balanced, multi-lineage blood production. However, a cohesive model that explains the relationships among these diverse HSC states remains elusive. Here, we combined single-cell transplantations of over 1,000 highly purified murine long-term HSCs with in-depth phenotyping of their clonal progeny to achieve a detailed, time-resolved understanding of heterogeneous reconstitution outcomes. We identified reconstitution kinetics as an overall unifying metric of HSC functional potency, with the most potent HSCs displaying the greatest delay in hematopoietic reconstitution. Importantly, a progressive acceleration in reconstitution kinetics was also associated with a gradual shift in mature cell production from platelet and erythro-myeloid bias to balanced, and eventually lymphoid bias. Serial single-cell transplantations of HSCs revealed a unidirectional acceleration in reconstitution kinetics accompanied by a gradual decline in functional potency of daughter HSCs, aligning diverse phenotypes along a linear hierarchical trajectory. Mathematical modeling, together with experimental modulation of lineage-biased blood production, demonstrated that apparent lineage biases actually arise from cell-extrinsic feedback regulation and clonal competition between slow- and fast-engrafting clones to occupy the limited compartment sizes of mature lineages. Our study reconciles multiple layers of HSC heterogeneity into a unifying framework, prompting a reevaluation of the meaning of lineage biases in both normal and diseased hematopoiesis, with broad implications for other regenerating tissues during development, homeostasis, and repair. |
| Keywords: | Animals, Mice |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2025.02.04.636388 |
| Date: | 5 February 2025 |
| Official Publication: | https://doi.org/10.1101/2025.02.04.636388 |
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