Diverse and Heritable Lineage Imprinting of Early Haematopoietic Progenitors

Nature. 2013 Apr 11;496(7444):229-32. doi: 10.1038/nature12013. Epub 2013 Apr 3.

Abstract

Haematopoietic stem cells (HSCs) and their subsequent progenitors produce blood cells, but the precise nature and kinetics of this production is a contentious issue. In one model, lymphoid and myeloid production branch after the lymphoid-primed multipotent progenitor (LMPP), with both branches subsequently producing dendritic cells. However, this model is based mainly on in vitro clonal assays and population-based tracking in vivo, which could miss in vivo single-cell complexity. Here we avoid these issues by using a new quantitative version of 'cellular barcoding' to trace the in vivo fate of hundreds of LMPPs and HSCs at the single-cell level. These data demonstrate that LMPPs are highly heterogeneous in the cell types that they produce, separating into combinations of lymphoid-, myeloid- and dendritic-cell-biased producers. Conversely, although we observe a known lineage bias of some HSCs, most cellular output is derived from a small number of HSCs that each generates all cell types. Crucially, in vivo analysis of the output of sibling cells derived from single LMPPs shows that they often share a similar fate, suggesting that the fate of these progenitors was imprinted. Furthermore, as this imprinting is also observed for dendritic-cell-biased LMPPs, dendritic cells may be considered a distinct lineage on the basis of separate ancestry. These data suggest a 'graded commitment' model of haematopoiesis, in which heritable and diverse lineage imprinting occurs earlier than previously thought.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics*
  • Cell Lineage*
  • DNA Barcoding, Taxonomic
  • Dendritic Cells / cytology
  • Dendritic Cells / metabolism
  • Genomic Imprinting*
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / metabolism*
  • Lymphocytes / cytology
  • Lymphocytes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Multipotent Stem Cells / cytology
  • Multipotent Stem Cells / metabolism
  • Myeloid Cells / cytology
  • Myeloid Cells / metabolism
  • Single-Cell Analysis