Haematopoiesis, the process of mature blood and immune cell production, is functionally organized as a hierarchy, with self-renewing haematopoietic stem cells and multipotent progenitor cells sitting at the very top1,2. Multiple models have been proposed as to what the earliest lineage choices are in these primitive haematopoietic compartments, the cellular intermediates, and the resulting lineage trees that emerge from them3,4,5,6,7,8,9,10. Given that the bulk of studies addressing lineage outcomes have been performed in the context of haematopoietic transplantation, current models of lineage branching are more likely to represent roadmaps of lineage potential than native fate. Here we use transposon tagging to clonally trace the fates of progenitors and stem cells in unperturbed haematopoiesis. Our results describe a distinct clonal roadmap in which the megakaryocyte lineage arises largely independently of other haematopoietic fates. Our data, combined with single-cell RNA sequencing, identify a functional hierarchy of unilineage- and oligolineage-producing clones within the multipotent progenitor population. Finally, our results demonstrate that traditionally defined long-term haematopoietic stem cells are a significant source of megakaryocyte-restricted progenitors, suggesting that the megakaryocyte lineage is the predominant native fate of long-term haematopoietic stem cells. Our study provides evidence for a substantially revised roadmap for unperturbed haematopoiesis, and highlights unique properties of multipotent progenitors and haematopoietic stem cells in situ.
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Gene Expression Omnibus
We are grateful to members of the Camargo and Klein laboratory for comments. A.R.F. is a Merck Fellow of the Life Sciences Research Foundation and a non-stipendiary European Molecular Biology Organization postdoctoral fellow. This work was supported by National Institutes of Health grants HL128850-01A1 and P01HL13147 to F.D.C. F.D.C. is a Leukemia and Lymphoma Society and a Howard Hughes Medical Institute Scholar. A.M.K. is supported by a Burroughs-Wellcome Fund CASI award, and by the Edward J. Mallinckrodt Fellowship.
Extended data figures
Sorted cells, clones identified and % DsRed in each population analysed. This table compiles the information of numbers of barcodes and % of DsRed from each mouse analysed, including the sorting logics for each population in each experiment.
Cluster differential expression analysis results. This set of tables contains the raw results of cluster differential expression analysis for each cluster under different tabs.