Mitotic History Reveals Distinct Stem Cell Populations and Their Contributions to Hematopoiesis

Cell Rep. 2016 Mar 29;14(12):2809-18. doi: 10.1016/j.celrep.2016.02.073. Epub 2016 Mar 17.

Abstract

Homeostasis of short-lived blood cells is dependent on rapid proliferation of immature precursors. Using a conditional histone 2B-mCherry-labeling mouse model, we characterize hematopoietic stem cell (HSC) and progenitor proliferation dynamics in steady state and following several types of induced stress. HSC proliferation following HSC transplantation into lethally irradiated mice is fundamentally different not only from native hematopoiesis but also from other stress contexts. Whereas transplantation promoted sustained, long-term proliferation of HSCs, both cytokine-induced mobilization and acute depletion of selected blood cell lineages elicited very limited recruitment of HSCs to the proliferative pool. By coupling mCherry-based analysis of proliferation history with multiplex gene expression analyses on single cells, we have found that HSCs can be stratified into four distinct subtypes. These subtypes have distinct molecular signatures and differ significantly in their reconstitution potentials, showcasing the power of tracking proliferation history when resolving functional heterogeneity of HSCs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Lineage
  • Cell Proliferation / drug effects
  • Collagen Type I / genetics
  • Collagen Type I, alpha 1 Chain
  • Doxorubicin / toxicity
  • Flow Cytometry
  • Gene Expression Regulation / drug effects
  • Genes, Reporter
  • Hematopoiesis / drug effects
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / metabolism
  • Immunophenotyping
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence
  • Mitosis*
  • Plasmids / genetics
  • Plasmids / metabolism
  • Real-Time Polymerase Chain Reaction
  • Transplantation, Homologous

Substances

  • Collagen Type I
  • Collagen Type I, alpha 1 Chain
  • Luminescent Proteins
  • red fluorescent protein
  • Doxorubicin