Rare multipotent haematopoietic stem cells (HSCs) in adult bone marrow with extensive self-renewal potential can efficiently replenish all myeloid and lymphoid blood cells1, securing long-term multilineage reconstitution after physiological and clinical challenges such as chemotherapy and haematopoietic transplantations2,3,4. HSC transplantation remains the only curative treatment for many haematological malignancies, but inefficient blood-lineage replenishment remains a major cause of morbidity and mortality5,6. Single-cell transplantation has uncovered considerable heterogeneity among reconstituting HSCs7,8,9,10,11, a finding that is supported by studies of unperturbed haematopoiesis2,3,4,12 and may reflect different propensities for lineage-fate decisions by distinct myeloid-, lymphoid- and platelet-biased HSCs7,8,9,10,13. Other studies suggested that such lineage bias might reflect generation of unipotent or oligopotent self-renewing progenitors within the phenotypic HSC compartment, and implicated uncoupling of the defining HSC properties of self-renewal and multipotency11,14. Here we use highly sensitive tracking of progenitors and mature cells of the megakaryocyte/platelet, erythroid, myeloid and B and T cell lineages, produced from singly transplanted HSCs, to reveal a highly organized, predictable and stable framework for lineage-restricted fates of long-term self-renewing HSCs. Most notably, a distinct class of HSCs adopts a fate towards effective and stable replenishment of a megakaryocyte/platelet-lineage tree but not of other blood cell lineages, despite sustained multipotency. No HSCs contribute exclusively to any other single blood-cell lineage. Single multipotent HSCs can also fully restrict towards simultaneous replenishment of megakaryocyte, erythroid and myeloid lineages without executing their sustained lymphoid lineage potential. Genetic lineage-tracing analysis also provides evidence for an important role of platelet-biased HSCs in unperturbed adult haematopoiesis. These findings uncover a limited repertoire of distinct HSC subsets, defined by a predictable and hierarchical propensity to adopt a fate towards replenishment of a restricted set of blood lineages, before loss of self-renewal and multipotency.
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We thank A. J. Mead, D. Atkinson, A. Giustacchini and N. Ashley for expert assistance with the Fluidigm array platform (WIMM Single Cell Core Facility is supported by the Medical Research Council (MRC) MHU (MC_UU_12009), the Oxford Single Cell Biology Consortium (MR/M00919X/1), the WT-ISSF (097813/Z/11/B#) and the WIMM Strategic Alliance awards G0902418 and MC_UU_12025); P. Sopp and S. A. Clark for expert flow cytometry technical support and cell-sorting services (WIMM FACS Core Facility is supported by the MRC HIU, MRC MHU (MC_UU_12009), NIHR Oxford BRC and the John Fell Fund (131/030 and 101/517), the EPA fund (CF182 and CF170) and by WIMM Strategic Alliance awards (G0902418 and MC_UU_12025)); the Biomedical Services at University of Oxford for animal technical support; the EMBL Monterotondo Gene Expression Service and Transgenic Core Facility for generating the Vwf-tdTomato BAC and the corresponding transgenic mouse line; N. Iscove for KitW41/W41 mice; A. Cumano for OP9-DL1 stromal cells; R. Drissen and S. Duarte for discussions and assistance with the preliminary phase of the studies; A. Hillen, B. Wu and T. Bouriez-Jones for technical assistance. This work was supported by Marie Curie Early Stage Researcher Fellowship (J.C.), the MRC UK (G0801073 and MC_UU_12009/5 to S.E.W.J. and G0701761, G0900892 and MC_UU_12009/7 to C.N.), the Swedish Research Council (S.E.W.J.), the Knut och Alice Wallenberg Foundation (WIRM; S.E.W.J.), the Tobias Foundation (S.E.W.J.), StratRegen KI (S.E.W.J.), Bloodwise (project grant 15006 to C.N.) and a BBSRC Project Grant (BB/M024350/1 to C.N.).
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Experimental Hematology (2019)