{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:48:39Z","timestamp":1760402919361,"version":"build-2065373602"},"reference-count":33,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,4,10]],"date-time":"2021-04-10T00:00:00Z","timestamp":1618012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010481","name":"Etablissement Fran\u00e7ais du Sang","doi-asserted-by":"publisher","award":["regular regional research budget 2017, 2018, 2019, 2020"],"award-info":[{"award-number":["regular regional research budget 2017, 2018, 2019, 2020"]}],"id":[{"id":"10.13039\/501100010481","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Alpha tocopherol acetate (\u03b1TOA) is an analogue of alpha tocopherol (\u03b1TOC) that exists in the form of an injectable drug. In the context of the metabolic hypothesis of stem cells, we studied the impact of \u03b1TOA on the metabolic energetic profile and functional properties of hematopoietic stem and progenitor cells. In ex vivo experiments performed on cord blood CD34+ cells, we found that \u03b1TOA effectively attenuates oxidative phosphorylation without affecting the glycolysis rate. This effect concerns complex I and complex II of the mitochondrial respiratory chain and is related to the relatively late increase (3 days) in ROS (Reactive Oxygen Species). The most interesting effect was the inhibition of Hypoxia-Inducible Factor (HIF)-2\u03b1 (Hexpression, which is a determinant of the most pronounced biological effect\u2014the accumulation of CD34+ cells in the G0 phase of the cell cycle. In parallel, better maintenance of the primitive stem cell activity was revealed by the expansion seen in secondary cultures (higher production of colony forming cells (CFC) and Severe Combined Immunodeficiency-mice (scid)-repopulating cells (SRC)). While the presence of \u03b1TOA enhanced the maintenance of Hematopoietic Stem Cells (HSC) and contained their proliferation ex vivo, whether it could play the same role in vivo remained unknown. Creating \u03b1TOC deficiency via a vitamin E-free diet in mice, we found an accelerated proliferation of CFC and an expanded compartment of LSK (lineagenegative Sca-1+cKit+) and SLAM (cells expressing Signaling Lymphocytic Activation Molecule family receptors) bone marrow cell populations whose in vivo repopulating capacity was decreased. These in vivo data are in favor of our hypothesis that \u03b1TOC may have a physiological role in the maintenance of stem cells. Taking into account that \u03b1TOC also exhibits an effect on proliferative capacity, it may also be relevant for the ex vivo manipulation of hematopoietic stem cells. For this purpose, low non-toxic doses of \u03b1TOA should be used.<\/jats:p>","DOI":"10.3390\/biom11040558","type":"journal-article","created":{"date-parts":[[2021,4,12]],"date-time":"2021-04-12T03:04:06Z","timestamp":1618196646000},"page":"558","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["\u03b1-Tocopherol Attenuates Oxidative Phosphorylation of CD34+ Cells, Enhances Their G0 Phase Fraction and Promotes Hematopoietic Stem and Primitive Progenitor Cell Maintenance"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8968-8873","authenticated-orcid":false,"given":"Laura","family":"Rodriguez","sequence":"first","affiliation":[{"name":"Etablissement Fran\u00e7ais du Sang Nouvelle Aquitaine, Place Am\u00e9lie Raba L\u00e9on, CS22010, CEDEX, 33075 Bordeaux, France"},{"name":"Inserm Bordeaux UMR 1035, 33000 Bordeaux, France"},{"name":"Universit\u00e9 de Bordeaux, 33000 Bordeaux, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pascale","family":"Duchez","sequence":"additional","affiliation":[{"name":"Etablissement Fran\u00e7ais du Sang Nouvelle Aquitaine, Place Am\u00e9lie Raba L\u00e9on, CS22010, CEDEX, 33075 Bordeaux, France"},{"name":"Inserm Bordeaux UMR 1035, 33000 Bordeaux, France"},{"name":"Universit\u00e9 de Bordeaux, 33000 Bordeaux, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0140-6371","authenticated-orcid":false,"given":"Nicolas","family":"Touya","sequence":"additional","affiliation":[{"name":"Etablissement Fran\u00e7ais du Sang Nouvelle Aquitaine, Place Am\u00e9lie Raba L\u00e9on, CS22010, CEDEX, 33075 Bordeaux, France"},{"name":"Inserm Bordeaux UMR 1035, 33000 Bordeaux, France"},{"name":"Universit\u00e9 de Bordeaux, 33000 Bordeaux, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christelle","family":"Debeissat","sequence":"additional","affiliation":[{"name":"Inserm Bordeaux UMR 1035, 33000 Bordeaux, France"},{"name":"Universit\u00e9 de Bordeaux, 33000 Bordeaux, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1451-8789","authenticated-orcid":false,"given":"Am\u00e9lie V.","family":"Guitart","sequence":"additional","affiliation":[{"name":"Inserm Bordeaux UMR 1035, 33000 Bordeaux, France"},{"name":"Universit\u00e9 de Bordeaux, 33000 Bordeaux, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1345-3776","authenticated-orcid":false,"given":"Jean-Max","family":"Pasquet","sequence":"additional","affiliation":[{"name":"Inserm Bordeaux UMR 1035, 33000 Bordeaux, France"},{"name":"Universit\u00e9 de Bordeaux, 33000 Bordeaux, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marija","family":"Vlaski-Lafarge","sequence":"additional","affiliation":[{"name":"Etablissement Fran\u00e7ais du Sang Nouvelle Aquitaine, Place Am\u00e9lie Raba L\u00e9on, CS22010, CEDEX, 33075 Bordeaux, France"},{"name":"Inserm Bordeaux UMR 1035, 33000 Bordeaux, France"},{"name":"Universit\u00e9 de Bordeaux, 33000 Bordeaux, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philippe","family":"Brunet de la Grange","sequence":"additional","affiliation":[{"name":"Etablissement Fran\u00e7ais du Sang Nouvelle Aquitaine, Place Am\u00e9lie Raba L\u00e9on, CS22010, CEDEX, 33075 Bordeaux, France"},{"name":"Inserm Bordeaux UMR 1035, 33000 Bordeaux, France"},{"name":"Universit\u00e9 de Bordeaux, 33000 Bordeaux, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zoran","family":"Ivanovic","sequence":"additional","affiliation":[{"name":"Etablissement Fran\u00e7ais du Sang Nouvelle Aquitaine, Place Am\u00e9lie Raba L\u00e9on, CS22010, CEDEX, 33075 Bordeaux, France"},{"name":"Inserm Bordeaux UMR 1035, 33000 Bordeaux, France"},{"name":"Universit\u00e9 de Bordeaux, 33000 Bordeaux, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1046\/j.1523-1747.1998.00273.x","article-title":"Effect of UVB on hydrolysis of alpha-tocopherol acetate to alpha-tocopherol in mouse skin","volume":"111","author":"Liebler","year":"1998","journal-title":"J. Invest. Dermatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"28666","DOI":"10.1074\/jbc.272.45.28666","article-title":"Modified low density lipoprotein enhances the secretion of bile salt-stimulated cholesterol esterase by human monocyte-macrophages. Species-specific difference in macrophage cholesteryl ester hydrolase","volume":"272","author":"Li","year":"1997","journal-title":"J. Biol. Chem."},{"doi-asserted-by":"crossref","unstructured":"Loncaric, D., Rodriguez, L., Debeissat, C., Touya, N., Labat, V., Villacreces, A., Bouzier-Sore, A.K., Pasquet, J.-M., de la Grange, P.B., and Vlaski-Lafarge, M. (2021). \u03b1-Tocopherol acetate attenuates mitochondrial oxygen consumption and maintains primitive cells within mesenchymal stromal cell population. Stem Cell Rev. Rep., in press.","key":"ref_3","DOI":"10.1007\/s12015-020-10111-9"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"677","DOI":"10.2217\/rme.13.65","article-title":"Respect the anaerobic nature of stem cells to exploit their potential in regenerative medicine","volume":"8","author":"Ivanovic","year":"2013","journal-title":"Regen. Med."},{"doi-asserted-by":"crossref","unstructured":"Ivanovic, Z., and Vlaski-Lafarge, M. (2015). Anaerobiosis and Stemness: An Evolutionary Paradigm, Elsevier.","key":"ref_5","DOI":"10.1016\/B978-0-12-800540-8.00014-4"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/ncb2730","article-title":"Quantitative imaging of haematopoietic stem and progenitor cell localization and hypoxic status in the bone marrow microenvironment","volume":"15","author":"Pivarnik","year":"2013","journal-title":"Nat. Cell. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4067162","DOI":"10.1155\/2019\/4067162","article-title":"Mitochondrial Role in Stemness and Differentiation of Hematopoietic Stem Cells","volume":"2019","author":"Papa","year":"2019","journal-title":"Stem Cells Int."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.3727\/096368910X552853","article-title":"Clinical-scale cultures of cord blood CD34(+) cells to amplify committed progenitors and maintain stem cell activity","volume":"20","author":"Ivanovic","year":"2011","journal-title":"Cell Transplant."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1038\/sj.ejcn.1602372","article-title":"Factors influencing blood concentration of retinol, alpha-tocopherol, vitamin C, and beta-carotene in the French participants of the SU.VI.MAX trial","volume":"60","author":"Faure","year":"2006","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1093\/ajcn\/84.2.375","article-title":"Distribution of serum concentrations of alpha-tocopherol and gamma-tocopherol in the US population","volume":"84","author":"Ford","year":"2006","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1634\/stemcells.2004-0351","article-title":"Very low O2 concentration (0.1%) favors G0 return of dividing CD34+ cells","volume":"24","author":"Hermitte","year":"2006","journal-title":"Stem Cells"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/nprot.2014.018","article-title":"Comprehensive measurement of respiratory activity in permeabilized cells using extracellular flux analysis","volume":"9","author":"Salabei","year":"2014","journal-title":"Nat Protoc."},{"key":"ref_13","first-page":"3346","article-title":"The selective antiproliferative effects of alpha-tocopheryl hemisuccinate and cholesteryl hemisuccinate on murine leukemia cells result from the action of the intact compounds","volume":"54","author":"Fariss","year":"1994","journal-title":"Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1016\/j.leukres.2008.09.035","article-title":"Apoptosis induction by (+)alpha-tocopheryl succinate in the absence or presence of all-trans retinoic acid and arsenic trioxide in NB4, NB4-R2 and primary APL cells","volume":"33","author":"Freitas","year":"2009","journal-title":"Leuk. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1002\/mnfr.200900386","article-title":"Tocopheryl quinones and mitochondria","volume":"54","author":"Gille","year":"2010","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.bcp.2008.04.003","article-title":"Ubiquinone and tocopherol: Dissimilar siblings","volume":"76","author":"Gille","year":"2008","journal-title":"Biochem. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/leu.2011.216","article-title":"(+)\u03b1-Tocopheryl succinate inhibits the mitochondrial respiratory chain complex I and is as effective as arsenic trioxide or ATRA against acute promyelocytic leukemia in vivo","volume":"26","author":"Pestana","year":"2012","journal-title":"Leukemias"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4324","DOI":"10.1038\/onc.2008.69","article-title":"Alpha-tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II","volume":"27","author":"Dong","year":"2008","journal-title":"Oncogene"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.stem.2013.08.011","article-title":"HIF-2\u03b1 protects human hematopoietic stem\/progenitors and acute myeloid leukemic cells from apoptosis induced by endoplasmic reticulum stress","volume":"13","author":"Foster","year":"2013","journal-title":"Cell Stem Cell."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1182\/blood-2003-02-0448","article-title":"The HIF family member EPAS1\/HIF-2alpha is required for normal hematopoiesis in mice","volume":"102","author":"Scortegagna","year":"2003","journal-title":"Blood"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1182\/blood-2013-02-484923","article-title":"Hif-2alpha is not essential for cell-autonomous hematopoietic stem cell maintenance","volume":"122","author":"Guitart","year":"2013","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"ra19","DOI":"10.1126\/scisignal.2003816","article-title":"Vitamin E Facilitates the Inactivation of the Kinase Akt by the Phosphatase PHLPP1","volume":"6","author":"Huang","year":"2013","journal-title":"Sci. Signal."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"580","DOI":"10.5966\/sctm.2015-0262","article-title":"Rapamycin-Induced Hypoxia Inducible Factor 2A Is Essential for Chondrogenic Differentiation of Amniotic Fluid Stem Cells","volume":"5","author":"Preitschopf","year":"2016","journal-title":"Stem Cells Transl. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.3389\/fphar.2019.01176","article-title":"Akt Regulated Phosphorylation of GSK-3\u03b2\/Cyclin D1, p21 and p27 Contributes to Cell Proliferation Through Cell Cycle Progression From G1 to S\/G2M Phase in Low-Dose Arsenite Exposed HaCat Cells","volume":"10","author":"Chen","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1952","DOI":"10.1096\/fj.02-0362fje","article-title":"\u03b3-Tocopherol inhibits human cancer cell cycle progression and cell proliferation by down-regulation of cyclins","volume":"16","author":"Gysin","year":"2002","journal-title":"FASEB J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1042\/bj3290675","article-title":"Synthesis and secretion of the pancreatic-type carboxyl ester lipase by human endothelial cells","volume":"329","author":"Li","year":"1998","journal-title":"Biochem. J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1016\/S0301-472X(01)00750-0","article-title":"Dissociation between stem cell phenotype and NOD\/SCID repopulating activity in human peripheral blood CD34(+) cells after ex vivo expansion","volume":"29","author":"Danet","year":"2001","journal-title":"Exp. Hematol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1634\/stemcells.22-5-716","article-title":"Simultaneous maintenance of human cord blood SCID-repopulating cells and expansion of committed progenitors at low O2 concentration (3%)","volume":"22","author":"Ivanovic","year":"2004","journal-title":"Stem Cells."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1182\/blood.V20.4.471.471","article-title":"Vitamin E deficiency in the monkey. IV. Further studies of the anemia with emphasis on bone marrow morphology","volume":"20","author":"Porter","year":"1962","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1182\/blood.V52.1.187.187","article-title":"Abnormalities of iron metabolism and erythropoiesis in vitamin E-deficient rabbits","volume":"52","author":"Chou","year":"1978","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1056\/NEJM196811282792202","article-title":"Edema and hemolytic anemia in premature infants. A vitamin E deficiency syndrome","volume":"279","author":"Ritchie","year":"1968","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.jpeds.2016.08.091","article-title":"50 Years Ago in The Journal of Pediatrics: Vitamin E Deficiency: A Previously Unrecognized Cause of Hemolytic Anemia in the Premature Infant","volume":"181","author":"Carey","year":"2017","journal-title":"J. Pediatr."},{"key":"ref_33","first-page":"1489","article-title":"Erythrocyte characteristics in vitamin E-responsive anemia of the owl monkey (Aotus trivirgatus)","volume":"43","author":"Brady","year":"1982","journal-title":"Am. J. Vet. Res."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/4\/558\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:12:17Z","timestamp":1760364737000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/4\/558"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,10]]},"references-count":33,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["biom11040558"],"URL":"https:\/\/doi.org\/10.3390\/biom11040558","relation":{},"ISSN":["2218-273X"],"issn-type":[{"type":"electronic","value":"2218-273X"}],"subject":[],"published":{"date-parts":[[2021,4,10]]}}}