Fate mapping of hematopoietic stem cells reveals two pathways of native thrombopoiesis

Mina N. F. Morcos, Congxin Li, Clara M. Munz, Alessandro Greco, Nicole Dressel, Susanne Reinhardt, Katrin Sameith, Andreas Dahl, Nils B. Becker, Axel Roers, Thomas Höfer () and Alexander Gerbaulet ()
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Mina N. F. Morcos: Institute for Immunology, Faculty of Medicine, TU Dresden
Congxin Li: Division of Theoretical Systems Biology, German Cancer Research Center
Clara M. Munz: Institute for Immunology, Faculty of Medicine, TU Dresden
Alessandro Greco: Division of Theoretical Systems Biology, German Cancer Research Center
Nicole Dressel: Institute for Immunology, Faculty of Medicine, TU Dresden
Susanne Reinhardt: DRESDEN-concept Genome Center, Center for Molecular and Cellular Bioengineering, TU Dresden
Katrin Sameith: DRESDEN-concept Genome Center, Center for Molecular and Cellular Bioengineering, TU Dresden
Andreas Dahl: DRESDEN-concept Genome Center, Center for Molecular and Cellular Bioengineering, TU Dresden
Nils B. Becker: Division of Theoretical Systems Biology, German Cancer Research Center
Axel Roers: Heidelberg University Hospital
Thomas Höfer: Division of Theoretical Systems Biology, German Cancer Research Center
Alexander Gerbaulet: Institute for Immunology, Faculty of Medicine, TU Dresden

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Hematopoietic stem cells (HSCs) produce highly diverse cell lineages. Here, we chart native lineage pathways emanating from HSCs and define their physiological regulation by computationally integrating experimental approaches for fate mapping, mitotic tracking, and single-cell RNA sequencing. We find that lineages begin to split when cells leave the tip HSC population, marked by high Sca-1 and CD201 expression. Downstream, HSCs either retain high Sca-1 expression and the ability to generate lymphocytes, or irreversibly reduce Sca-1 level and enter into erythro-myelopoiesis or thrombopoiesis. Thrombopoiesis is the sum of two pathways that make comparable contributions in steady state, a long route via multipotent progenitors and CD48hi megakaryocyte progenitors (MkPs), and a short route from HSCs to developmentally distinct CD48−/lo MkPs. Enhanced thrombopoietin signaling differentially accelerates the short pathway, enabling a rapid response to increasing demand. In sum, we provide a blueprint for mapping physiological differentiation fluxes from HSCs and decipher two functionally distinct pathways of native thrombopoiesis.

Date: 2022
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DOI: 10.1038/s41467-022-31914-z

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