title: Self-renewal of a purified Tie2+ hematopoietic stem cell population relies on mitochondrial clearance.
abstract: A single hematopoietic stem cell (HSC) is capable of reconstituting hematopoiesis and maintaining homeostasis by balancing self-renewal and cell differentiation. The mechanisms of HSC division balance, however, are not yet defined. Here we demonstrate, by characterizing at the single-cell level a purified and minimally heterogeneous murine Tie2+HSC population, that these top hierarchical HSCs preferentially undergo symmetric divisions. The induction of mitophagy, a quality control process in mitochondria, plays an essential role in self-renewing expansion of Tie2+HSCs. Activation of the PPAR (peroxisome proliferator-activated receptor)-fatty acid oxidation pathway promotes expansion of Tie2+HSCs through enhanced Parkin recruitment in mitochondria. These metabolic pathways are conserved in human TIE2+HSCs. Our data thus identify mitophagy as a key mechanism of HSC expansion and suggest potential methods of cell-fate manipulation through metabolic pathways.
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Ito
authors.affiliation: Center for Systems Biology, Advanced Microscopy Program, Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Turcotte
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Departments of Cell Biology and Stem Cell Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Cui
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Samuel E
authors.initials: SE
authors.lastname: Zimmerman
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Departments of Cell Biology and Stem Cell Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pinho
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Departments of Cell Biology and Stem Cell Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Mizoguchi
authors.affiliation: Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, School of Medicine, Keio University, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Arai
authors.affiliation: Center for Systems Biology, Advanced Microscopy Program, Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Runnels
authors.affiliation: Center for Systems Biology, Advanced Microscopy Program, Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Clemens
authors.initials: C
authors.lastname: Alt
authors.affiliation: Department of Pathology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Teruya-Feldstein
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Mar
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Rajat
authors.initials: R
authors.lastname: Singh
authors.affiliation: Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, School of Medicine, Keio University, Japan.|Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
authors.affiliation: Center for Systems Biology, Advanced Microscopy Program, Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Lin
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Departments of Cell Biology and Stem Cell Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Frenette
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA. keisuke.ito@einstein.yu.edu.|Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Departments of Cell Biology and Stem Cell Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ito
mesh_terms: D000818:Animals; D000066673:Cell Self Renewal; D002469:Cell Separation; D005227:Fatty Acids / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000378:metabolism; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000737:chemistry / Q000502:physiology*; D053858:Metabolic Networks and Pathways; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000502:physiology*; D063306:Mitophagy / Q000235:genetics / Q000502:physiology*; D010084:Oxidation-Reduction; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000032:analysis; D059010:Single-Cell Analysis; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D047492:Peroxisome Proliferator-Activated Receptors; D049452:Green Fluorescent Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D042787:Receptor, TIE-2; C079086:Tek protein, mouse