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STEM CELL BIOLOGY

REDD1 is a gatekeeper of murine hematopoietic stem cell functions during stress responses

Leukemia volume 36, pages 2140–2143 (2022)Cite this article

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Blood cells are continuously produced throughout life by hematopoietic stem cells (HSC) that are quiescent and possess a long-term self-renewal potential. Upon acute stress, HSC are activated to proliferate, differentiate hereby allowing organism survival [1]. However, HSC activation need to be resolved soon after stress to protect HSC integrity and to prevent their exhaustion. mTOR and reactive oxygen species (ROS) are the two major pathways activated following stress. Their over-activation leads to defect in HSC self-renewal potential, HSC exhaustion and potentially leukemic transformation, thus they need to be inactivated at the end of the stress episode [2, 3]. mTOR activation is inhibited in part by a negative feedback triggered by the MEK1 kinase [4]. Similarly, ROS levels can be lowered by mTOR dependent [2, 4] and independent mechanisms [5]. Recently, HMCES, a stress response protein involved in DNA damage response pathway, was shown to protect HSC genome integrity after stress [6], suggesting that stress response proteins play crucial role in HSC maintenance. Another well-known stress response protein is the “regulated in development and DNA damage 1” (REDD1) protein, encoded by Ddit4 [7]. REDD1 expression is induced after genotoxic stress such as irradiation (IR) or chemotherapy (5-FluoroUracile, 5-FU). Interestingly, REDD1 and mTOR are connected since REDD1 inhibits mTOR activation and controls ROS production [8]. High expression of REDD1 is correlated with bad prognosis in acute myeloid leukemia (AML) making REDD1 a new putative target in treatment against AML, but REDD1 functions are still not depicted in normal and leukemic hematopoiesis [9, 10]. Here, we show, using a Redd1−/− mouse model, that REDD1 is required to protect HSC regenerative capacities after genotoxic stress, by regulating ROS levels and avoiding HSC exhaustion.

Interestingly persistent increased ROS levels 8 weeks after IR in Redd1−/− cells did not affect the phenotype nor the cellularity of hematopoietic cells, in blood and in the BM (Supplementary Fig. 6A–E). However, persistent high ROS levels and p38MAPK activation in HSC are associated with defects in hematopoietic reconstitution and self-renewal potential [14], therefore, we tested the HSC functions of Redd1−/− and Redd1wt mice after genotoxic stress. Eight weeks after IR, sorted LSK cells from both mouse strains were transplanted in recipient mice in competition as described in Supplementary Fig. 7A. Irradiated-Redd1−/− LSK cells generated less blood progeny in comparison to irradiated-Redd1wt LSK cells (Fig. 2D) indicating a defect in HSC reconstitution potential. 16 weeks post-graft, when gated in CD45.2+ subsets, the proportion of mature cells in the blood was similar in both mouse genotypes (Supplementary Fig. 7B). In the BM, the percentage and the absolute number of donor cells (CD45.2+) and donor LSK and SLAM-HSC from Redd1−/− genotype was drastically reduced in comparison to cells generated from Redd1wt LSK cells (Supplementary Fig. 7C, D), showing that normal levels of REDD1 are necessary for a robust long-term hematopoietic development and the maintenance of HSC numbers after stress.

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Fig. 1: REDD1 deficiency induces a partial loss of HSC self-renewal potential and leads to HSC exhaustion upon genotoxic stress.
Fig. 2: The increased ROS levels after irradiation in Redd1−/− mice are responsible for the defects of HSC response to stress in absence of REDD1.

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Acknowledgements

This work was supported by the Radiobiology Program of the French Alternative Energies and Atomic Energy Commission (CEA) and the Ligue régionale contre le cancer (comité 92) to M-LA and by grants from INSERM and by the Ligue Nationale contre le Cancer (LNCC). EH is a fellow of LNCC and RK, of Canceropôle Ile-de-France. We thank all members of Pflumio’ lab in particular Dr Haddad and Dr Calvo for their scientific advices and their support and Dr Gallouet (CEA-IDMIT) for her precious help. We also thank Dr Guitart from Bordeaux University for her help. We are grateful to Dr Roméo, Dr Lewandowski and Dr Carles for constant support and interest.

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  1. Marie-Laure Arcangeli

    Present address: Université Côte d’Azur, C3M/INSERM, U1065, Nice, France

Authors and Affiliations

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

    Vilma Barroca, Elia Henry, Nathalie Dechamps, Laurent Renou, Rohan Kulkarni, Saiyirami Devanand, Françoise Pflumio & Marie-Laure Arcangeli

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

    Vilma Barroca, Elia Henry, Nathalie Dechamps, Laurent Renou, Rohan Kulkarni, Saiyirami Devanand, Françoise Pflumio & Marie-Laure Arcangeli

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

    Vilma Barroca, Elia Henry, Laurent Renou, Rohan Kulkarni, Françoise Pflumio & Marie-Laure Arcangeli

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

    Laurent Renou, Arnaud Jacquel, Guillaume Robert, Patrick Auberger, Françoise Pflumio & Marie-Laure Arcangeli

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

    Paul Chaintreuil, Arnaud Jacquel, Guillaume Robert & Patrick Auberger

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  1. Vilma Barroca
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Contributions

VB, M-LA, EH and ND performed experiments with the help of PC, SD and RK. M-LA designed and analyzed data. AJ, GR and PA corrected the manuscript. FP and M-LA wrote the manuscript.

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Correspondence to Marie-Laure Arcangeli.

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Barroca, V., Henry, E., Dechamps, N. et al. REDD1 is a gatekeeper of murine hematopoietic stem cell functions during stress responses. Leukemia 36, 2140–2143 (2022). https://doi.org/10.1038/s41375-022-01609-x

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