Specification of haematopoietic stem cell fate via modulation of mitochondrial activity

• Published in: Nature communications Vol. 7; no. 1; pp. 13125 - 9
• Main Authors: Vannini, Nicola, Girotra, Mukul, Naveiras, Olaia, Nikitin, Gennady, Campos, Vasco, Giger, Sonja, Roch, Aline, Auwerx, Johan, Lutolf, Matthias P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.10.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/100; 631/532/1542; 631/532/2441; 631/80/39; 631/80/642/333/1465; Autophagy; Bioengineering; Bone marrow; Cell cycle; Humanities and Social Sciences; Life sciences; Metabolism; Microscopy; Mitochondria; multidisciplinary; Phosphorylation; Science; Science (multidisciplinary); Stem cells; Switzerland
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms13125

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. Haematopoietic stem cells rely on glycolysis for their energy demands but whether this affects their fate is unknown. Here, the authors show that forcing the cells to rely on glycolysis is important for self-renewal and that this involves a reduction in mitochondrial mass.