The Antioxidant TEMPOL Protects Human Hematopoietic Stem Cells From Culture-Mediated Loss of Functions

Author:

Henry Elia123,Picou Frédéric456,Barroca Vilma123,Dechamps Nathalie12,Sobrino Steicy7,Six Emmanuelle7,Gobeaux Camille8,Auberger Patrick910,Hérault Olivier46,Pflumio Françoise139,Arcangeli Marie-Laure123910ORCID

Affiliation:

1. Université de Paris, INSERM, CEA, Stabilité Génétique Cellules Souches et Radiations , F-92260 Fontenay-aux-Roses , France

2. Université Paris-Saclay, INSERM, CEA, Stabilité Génétique Cellules Souches et Radiations , F-92260 Fontenay-aux-Roses , France

3. Laboratoire des cellules Souches Hématopoïétiques et des Leucémies, Equipe Niche et Cancer dans l’Hématopoïèse, équipe labellisée Ligue Nationale Contre le Cancer, UMR1274-E008, INSERM, CEA , F-92265 Fontenay-aux Roses , France

4. CNRS EMR 7001 LNOx Leukemic Niche and Redox Metabolism , Tours , France

5. EA 7501, Université de Tours , Tours , France

6. Department of Biological Hematology, Tours University Hospital , Tours , France

7. Human Lymphohematopoiesis Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163 , Paris , France

8. Biochemistry Department/Diagnostic Biologique Automatisé (SDBA), DMU sBioPhyGen, Cochin Hospital-Université de Paris

9. OPALE Carnot Institute, The Organization for Partnerships in Leukemia, Saint-Louis Hospital , 75010 Paris , France

10. Université Côte d’Azur, C3M/INSERM U1065 , Nice , France

Abstract

Abstract In a steady state, hematopoietic stem cells (HSC) exhibit very low levels of reactive oxygen species (ROS). Upon stress, HSC get activated and enter into proliferation and differentiation process to ensure blood cell regeneration. Once activated, their levels of ROS increase, as messengers to mediate their proliferation and differentiation programs. However, at the end of the stress episode, ROS levels need to return to normal to avoid HSC exhaustion. It was shown that antioxidants can prevent loss of HSC self-renewal potential in several contexts such as aging or after exposure to low doses of irradiation suggesting that antioxidants can be used to maintain HSC functional properties upon culture-induced stress. Indeed, in humans, HSC are increasingly used for cell and gene therapy approaches, requiring them to be cultured for several days. As expected, we show that a short culture period leads to drastic defects in HSC functional properties. Moreover, a switch of HSC transcriptional program from stemness to differentiation was evidenced in cultured HSC. Interestingly, cultured-HSC treated with 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (4-hydroxy-TEMPO or Tempol) exhibited a higher clonogenic potential in secondary colony forming unit cell (CFU-C) assay and higher reconstitution potential in xenograft model, compared to untreated cultured-HSC. By transcriptomic analyses combined with serial CFU-C assays, we show that Tempol, which mimics superoxide dismutase, protects HSC from culture-induced stress partly through VEGFα signaling. Thus, we demonstrate that adding Tempol leads to the protection of HSC functional properties during ex vivo culture.

Funder

INSERM

Ligue Nationale contre le Cancer

Ligue Régionale Contre le Cancer

European Network RISK-IR

EUR G.E.N.E

Université de Paris

French Government

Investments for the Future

Ligue Nationale Contre le Cancer and a Doctoral Mentor

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,General Medicine

Reference56 articles.

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