ArticleCell stem cell2024
A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate.
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Article in Cell stem cell, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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41citing papers in PubMed
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41 citing papers in PubMed, 48 citations in OpenAlex.
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- Hepatocyte hedgehog signaling controls ferroptosis to alleviate aging-related organ dysfunction.JCI insight · 2026Article
- Sterol biosynthesis, brain development, and disease.The Journal of clinical investigation · 2026Review
- Extracellular vesicles in solid tumors: from tumor ecology to engineered therapeutics.Molecular cancer · 2026Review
- Extracellular vesicle cargo dynamics in the bone marrow microenvironment: from hematopoietic homeostasis to malignant transformation.Extracellular vesicle · 2026Article
- Advancements in extracellular vesicle research.Extracellular vesicle · 2026Article
- A self-powered chloroplast-driven nanophotosystem for treating skin photoaging through rejuvenating mitochondria and revitalizing senescent fibroblasts.Journal of nanobiotechnology · 2026Article
- Vesicles for cell crosstalk in bone: composition, function and application.Science China. Life sciences · 2026Review
- Dysregulation of Extracellular Vesicle Concentration, MicroRNAs, and Surface Proteins in Patients With Niemann-Pick Disease Type C.Journal of extracellular biology · 2026Article
- NCOA2 promotes the return of hematopoietic stem cells to quiescence after irradiation stress by regulating FOXO3a-dependent mitophagy.HemaSphere · 2026Article
- Intrinsic and niche-dependent metabolic regulation of haematopoietic stem cells and implications for leukaemogenesis.Nature cell biology · 2026Review
- Nonoxidative pentose phosphate pathway regulates CD8Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Elevated endocytic trafficking mediated by GPRASP2 maintains HSC fidelity.bioRxiv : the preprint server for biology · 2026Article
- Activation of a branched-chain amino acid rheostat restores replication-dependent hematopoietic stem cell fitness.Cell stem cell · 2026Article
- L-Theanine ameliorates high-protein diet-associated hepatic glucose and lipid metabolic alterations by promoting fatty acid β-oxidation and suppressing lipid synthesis and gluconeogenesis in rats.Current research in food science · 2026Article
- Apoptotic vesicles rectify senile bone-fat imbalance by activating Thy1-ERK-TAZ axis.Journal of nanobiotechnology · 2025Article
- Multi-modal label-free imaging of cellular metabolism and oxidative stress in 3D brain tissue models.Communications biology · 2025Article
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Authors and funding
21 authors at 7 institutions in 4 countries.
Massimo BonoraRuth 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, Albert Einstein College of Medicine-Montefiore Health System, Bronx, NY 10461, USA.
Claudia MorgantiRuth 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, Albert Einstein College of Medicine-Montefiore Health System, Bronx, NY 10461, USA.
Nick van GastelDepartment 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.
Kyoko ItoRuth 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, Albert Einstein College of Medicine-Montefiore Health System, Bronx, NY 10461, USA.
Enrica CaluraDepartment of Biology, University of Padova, 35121 Padua, Italy.
Ilaria ZanollaDepartment of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy.
Letizia FerroniMaria Cecilia Hospital, GVM Care & Research, Cotignola, 48033 Ravenna, Italy.
Yang ZhangDepartment of Biomedical Engineering, Tufts University, 4 Colby St, Medford, MA 02155, USA.
Yookyung JungDepartment 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.
Gabriele SalesDepartment of Biology, University of Padova, 35121 Padua, Italy.
Paolo MartiniDepartment of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy.
Takahisa NakamuraDivisions 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 and Cancer, Tohoku University, Sendai 980-8575, Japan.
Francesco Massimo LasorsaDepartment of Biosciences Biotechnologies and Environment University of Bari and Institute of Biomembranes Bioenergetics and Molecular Biotechnologies, Consiglio Nazionale delle Ricerche, 70125 Bari, Italy.
Toren FinkelAging Institute and Department of Medicine, University of Pittsburgh School of Medicine/University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA.
Charles P LinCenter for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Barbara ZavanMaria 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.
Paolo PintonDepartment 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.
Irene GeorgakoudiDepartment of Biomedical Engineering, Tufts University, 4 Colby St, Medford, MA 02155, USA.
Chiara RomualdiDepartment of Biology, University of Padova, 35121 Padua, Italy.
David T ScaddenDepartment 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.
Keisuke ItoRuth 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, Albert Einstein College of Medicine-Montefiore Health System, Bronx, NY 10461, USA; Montefiore Einstein Comprehensive Cancer Center and Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: keisuke.ito@einsteinmed.edu.
Albert Einstein College of Medicine · USHarvard University · USTufts University · USCincinnati Children's Hospital Medical Center · USUniversity of Ferrara · ITUniversity of Padua · ITUniversity of Pittsburgh Medical Center · US
Funding
WORD PROCESSORP30CA013330 · NCI · YESHIVA UNIVERSITY · PI Ulrich Steidl · 1985 to 2026
$111.2MTranscriptional and epigenetic heterogeneity of stem/progenitor cellsP01HL131477 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI Jason Daniel Buenrostro · 2017 to 2026
$24.6MProject 3: Single Cell Measures of Intratumor Diversity for Optimal Breast Cancer TherapyU54CA193461 · NCI · DANA-FARBER CANCER INST · PI HOLLAND, ERIC C. · 2015 to 2020
$11.2MIn Vivo Sickle Cell Vasoocclusion: Adhesion MechanismsR01HL069438 · NHLBI · MOUNT SINAI SCHOOL OF MEDICINE OF NYU · PI KELLY, LIBUSHA · 2001 to 2024
$9.5MThe Roles of Lipid Metabolism in the Maintenance of Hematopoietic Stem CellsR01DK098263 · NIDDK · ALBERT EINSTEIN COLLEGE OF MEDICINE, INC · PI Keisuke Ito · 2013 to 2026
$5.2MDissecting the canonical and non-canonical functions of Tet2 in hematopoietic stem cells and hematologic disordersR01HL148852 · NHLBI · ALBERT EINSTEIN COLLEGE OF MEDICINE · PI Meelad Dawlaty, Keisuke Ito · 2019 to 2026
$4.4MProbe-based two photon microscopy for functional, label-free early cancer diagnosisR01EB030061 · NIBIB · TUFTS UNIVERSITY MEDFORD · PI BEN-YAKAR, ADELA, GEORGAKOUDI, IRENE · 2020 to 2023
$3.2MSingle cell approach to uncovering factors regulating HSC division symmetry in vivoR01DK115577 · NIDDK · ALBERT EINSTEIN COLLEGE OF MEDICINE, INC · PI ITO, KEISUKE, LIN, CHARLES P. · 2017 to 2021
$2.9MRole of extracellular vesicles in the regulation of immunometabolism in obesityR01DK123181 · NIDDK · CINCINNATI CHILDRENS HOSP MED CTR · PI NAKAMURA, TAKAHISA · 2020 to 2023
$2.7MAcquisition of Leica confocal/multiphoton microscopeS10OD021624 · OD · TUFTS UNIVERSITY MEDFORD · PI GEORGAKOUDI, IRENE · 2016 to 2016
$600kNCI NIH HHS P30 CA013330NCI NIH HHS U54 CA193461NHLBI NIH HHS P01 HL131477NHLBI NIH HHS R01 HL069438NHLBI NIH HHS R01 HL148852NIBIB NIH HHS R01 EB030061NIDDK NIH HHS R01 DK098263NIDDK NIH HHS R01 DK115577NIDDK NIH HHS R01 DK123181NIH HHS S10 OD021624
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.
Indexed as
Extracellular VesiclesHematopoietic Stem CellsCell DifferentiationCell Self RenewalNADPNADPcholesterolexosomesextracellular vesiclesfate determinationfatty acid oxidationhematopoietic stem cellHSC self-renewalmetabolismmitochondriaNADPH
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