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A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate.
Bonora, Massimo; Morganti, Claudia; van Gastel, Nick; Ito, Kyoko; Calura, Enrica; Zanolla, Ilaria; Ferroni, Letizia; Zhang, Yang; Jung, Yookyung; Sales, Gabriele; Martini, Paolo; Nakamura, Takahisa; Lasorsa, Francesco Massimo; Finkel, Toren; Lin, Charles P; Zavan, Barbara; Pinton, Paolo; Georgakoudi, Irene; Romualdi, Chiara; Scadden, David T; Ito, Keisuke.
Afiliação
  • Bonora M; Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Departments of Oncology and Medicine,
  • Morganti C; Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Departments of Oncology and Medicine,
  • van Gastel N; Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; de Duve Institute, UCLouvain, 1200 Brussels, Belgium.
  • Ito K; Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Departments of Oncology and Medicine,
  • Calura E; Department of Biology, University of Padova, 35121 Padua, Italy.
  • Zanolla I; Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy.
  • Ferroni L; Maria Cecilia Hospital, GVM Care & Research, Cotignola, 48033 Ravenna, Italy.
  • Zhang Y; Department of Biomedical Engineering, Tufts University, 4 Colby St, Medford, MA 02155, USA.
  • Jung Y; Department of Biomedical Engineering, Tufts University, 4 Colby St, Medford, MA 02155, USA; Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • Sales G; Department of Biology, University of Padova, 35121 Padua, Italy.
  • Martini P; Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy.
  • Nakamura T; Divisions of Endocrinology and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Department of Metabolic Bioregulation, Institute of Development, Aging an
  • Lasorsa FM; Department of Biosciences Biotechnologies and Environment University of Bari and Institute of Biomembranes Bioenergetics and Molecular Biotechnologies, Consiglio Nazionale delle Ricerche, 70125 Bari, Italy.
  • Finkel T; Aging Institute and Department of Medicine, University of Pittsburgh School of Medicine/University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA.
  • Lin CP; Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • Zavan B; Maria Cecilia Hospital, GVM Care & Research, Cotignola, 48033 Ravenna, Italy; Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy; Translational Medicine Department, University of Ferrara, 44121 Ferrara, Italy.
  • Pinton P; Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; Maria Cecilia Hospital, GVM Care & Research, Cotignola, 48033 Ravenna, Italy; Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy.
  • Georgakoudi I; Department of Biomedical Engineering, Tufts University, 4 Colby St, Medford, MA 02155, USA.
  • Romualdi C; Department of Biology, University of Padova, 35121 Padua, Italy.
  • Scadden DT; Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Ito K; Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Departments of Oncology and Medicine,
Cell Stem Cell ; 31(3): 359-377.e10, 2024 03 07.
Article em En | MEDLINE | ID: mdl-38458178
ABSTRACT
Mitochondrial fatty acid oxidation (FAO) is essential for hematopoietic stem cell (HSC) self-renewal; however, the mechanism by which mitochondrial metabolism controls HSC fate remains unknown. Here, we show that within the hematopoietic lineage, HSCs have the largest mitochondrial NADPH pools, which are required for proper HSC cell fate and homeostasis. Bioinformatic analysis of the HSC transcriptome, biochemical assays, and genetic inactivation of FAO all indicate that FAO-generated NADPH fuels cholesterol synthesis in HSCs. Interference with FAO disturbs the segregation of mitochondrial NADPH toward corresponding daughter cells upon single HSC division. Importantly, we have found that the FAO-NADPH-cholesterol axis drives extracellular vesicle (EV) biogenesis and release in HSCs, while inhibition of EV signaling impairs HSC self-renewal. These data reveal the existence of a mitochondrial NADPH-cholesterol axis for EV biogenesis that is required for hematopoietic homeostasis and highlight the non-stochastic nature of HSC fate determination.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Células-Tronco Hematopoéticas / Vesículas Extracelulares Idioma: En Revista: Cell Stem Cell Ano de publicação: 2024 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Células-Tronco Hematopoéticas / Vesículas Extracelulares Idioma: En Revista: Cell Stem Cell Ano de publicação: 2024 Tipo de documento: Article