Hierarchically related lineage-restricted fates of multipotent haematopoietic stem cells

Nature. 2018 Feb 1;554(7690):106-111. doi: 10.1038/nature25455. Epub 2018 Jan 3.


Rare multipotent haematopoietic stem cells (HSCs) in adult bone marrow with extensive self-renewal potential can efficiently replenish all myeloid and lymphoid blood cells, securing long-term multilineage reconstitution after physiological and clinical challenges such as chemotherapy and haematopoietic transplantations. HSC transplantation remains the only curative treatment for many haematological malignancies, but inefficient blood-lineage replenishment remains a major cause of morbidity and mortality. Single-cell transplantation has uncovered considerable heterogeneity among reconstituting HSCs, a finding that is supported by studies of unperturbed haematopoiesis and may reflect different propensities for lineage-fate decisions by distinct myeloid-, lymphoid- and platelet-biased HSCs. 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 multipotency. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD34
  • B-Lymphocytes / cytology
  • Blood Platelets / cytology
  • CD48 Antigen / deficiency
  • Cell Lineage*
  • Cell Self Renewal
  • Erythroid Cells / cytology
  • Female
  • Hematopoiesis*
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / metabolism
  • Male
  • Megakaryocytes / cytology
  • Mice
  • Multipotent Stem Cells / cytology*
  • Multipotent Stem Cells / metabolism
  • Myeloid Cells / cytology
  • Signaling Lymphocytic Activation Molecule Family Member 1 / metabolism
  • T-Lymphocytes / cytology


  • Antigens, CD34
  • CD48 Antigen
  • Cd48 protein, mouse
  • Slamf1 protein, mouse
  • Signaling Lymphocytic Activation Molecule Family Member 1