title: Specification of haematopoietic stem cell fate via modulation of mitochondrial activity.
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.
authors.affiliation: Laboratory of Stem Cell Bioengineering, Institute of Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.|Laboratory of Regenerative Hematopoiesis (GR-NAVEIRAS), Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Nicola
authors.initials: N
authors.lastname: Vannini
authors.affiliation: Laboratory of Stem Cell Bioengineering, Institute of Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Mukul
authors.identifier: 0000-0003-0937-3674
authors.initials: M
authors.lastname: Girotra
authors.affiliation: Laboratory of Regenerative Hematopoiesis (GR-NAVEIRAS), Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.|Departments of Medicine and Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), CH-1011 Lausanne, Switzerland.
authors.forename: Olaia
authors.identifier: 0000-0003-3434-0022
authors.initials: O
authors.lastname: Naveiras
authors.affiliation: Laboratory of Stem Cell Bioengineering, Institute of Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Gennady
authors.initials: G
authors.lastname: Nikitin
authors.affiliation: Laboratory of Regenerative Hematopoiesis (GR-NAVEIRAS), Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Vasco
authors.initials: V
authors.lastname: Campos
authors.affiliation: Laboratory of Stem Cell Bioengineering, Institute of Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Sonja
authors.initials: S
authors.lastname: Giger
authors.affiliation: Laboratory of Stem Cell Bioengineering, Institute of Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Aline
authors.initials: A
authors.lastname: Roch
authors.affiliation: Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.affiliation: Laboratory of Stem Cell Bioengineering, Institute of Bioengineering, School of Life Sciences and School of Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.|Institute of Chemical Sciences and Engineering, School of Basic Science, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Matthias P
authors.identifier: 0000-0002-5898-305X
authors.initials: MP
authors.lastname: Lutolf
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D004579:Electron Transport / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D006019:Glycolysis / Q000187:drug effects; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000145:classification* / Q000166:cytology / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D061209:Proton Ionophores / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D055153:Stem Cell Niche / Q000235:genetics; D014475:Uncoupling Agents / Q000494:pharmacology*; D014916:Whole-Body Irradiation
chemical_list: D015415:Biomarkers; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D061209:Proton Ionophores; D011956:Receptors, Cell Surface; C489997:Tomm20 protein, mouse; D014475:Uncoupling Agents; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone