Specification of haematopoietic stem cell fate via modulation of mitochondrial activity

Nat Commun. 2016 Oct 12:7:13125. doi: 10.1038/ncomms13125.

Abstract

Haematopoietic stem cells (HSCs) differ from their committed progeny by relying primarily on anaerobic glycolysis rather than mitochondrial oxidative phosphorylation for energy production. However, whether this change in the metabolic program is the cause or the consequence of the unique function of HSCs remains unknown. Here we show that enforced modulation of energy metabolism impacts HSC self-renewal. Lowering the mitochondrial activity of HSCs by chemically uncoupling the electron transport chain drives self-renewal under culture conditions that normally induce rapid differentiation. We demonstrate that this metabolic specification of HSC fate occurs through the reversible decrease of mitochondrial mass by autophagy. Our data thus reveal a causal relationship between mitochondrial metabolism and fate choice of HSCs and also provide a valuable tool to expand HSCs outside of their native bone marrow niches.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / drug effects
  • Autophagy / genetics
  • Biomarkers / metabolism
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / metabolism
  • Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / pharmacology
  • Cell Differentiation / drug effects
  • Cell Lineage / genetics
  • Cell Proliferation / drug effects
  • Electron Transport / drug effects*
  • Female
  • Flow Cytometry
  • Glycolysis / drug effects
  • Hematopoietic Stem Cell Transplantation*
  • Hematopoietic Stem Cells / classification*
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism
  • Membrane Transport Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Oxidative Phosphorylation / drug effects*
  • Proton Ionophores / pharmacology
  • Receptors, Cell Surface / metabolism
  • Stem Cell Niche / genetics
  • Uncoupling Agents / pharmacology*
  • Whole-Body Irradiation

Substances

  • Biomarkers
  • Membrane Transport Proteins
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Proton Ionophores
  • Receptors, Cell Surface
  • Tomm20 protein, mouse
  • Uncoupling Agents
  • Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone