NFAT5 counters long-term IFN-1 responses in hematopoietic stem cells to preserve reconstitution potential.

Autor:	Traveset L; Department of Medicine and Life Sciences, Immunology Unit, Universitat Pompeu Fabra, Barcelona, Spain., Cerdán Porqueras V; Department of Medicine and Life Sciences, Immunology Unit, Universitat Pompeu Fabra, Barcelona, Spain., Huerga Encabo H; Department of Medicine and Life Sciences, Immunology Unit, Universitat Pompeu Fabra, Barcelona, Spain., Avalle S; Department of Medicine and Life Sciences, Immunology Unit, Universitat Pompeu Fabra, Barcelona, Spain., Esteve-Codina A; Bioinformatics unit, Centro Nacional de Análisis Genómico, Centre for Genomic Regulation, Barcelona Institute for Science and Technology, Barcelona, Spain.; Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain., Fornas O; Department of Medicine and Life Sciences, Flow Cytometry Unit, Universitat Pompeu Fabra, Centre for Genomic Regulation, Barcelona Institute for Science and Technology, Barcelona, Spain., Aramburu J; Department of Medicine and Life Sciences, Immunology Unit, Universitat Pompeu Fabra, Barcelona, Spain., Lopez-Rodriguez C; Department of Medicine and Life Sciences, Immunology Unit, Universitat Pompeu Fabra, Barcelona, Spain.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2024 Nov 12; Vol. 8 (21), pp. 5510-5526.
DOI:	10.1182/bloodadvances.2023011306
Abstrakt:	Abstract: Hematopoietic stem cells (HSCs) readily recover from acute stress, but persistent stress can reduce their viability and long-term potential. Here, we show that the nuclear factor of activated T cells 5 (NFAT5), a transcription modulator of inflammatory responses, protects the HSC pool under stress. NFAT5 restrains HSC differentiation to multipotent progenitors after bone marrow transplantation and bone marrow ablation with ionizing radiation or chemotherapy. Correspondingly, NFAT5-deficient HSCs fail to support long-term reconstitution of hematopoietic progenitors and mature blood cells after serial transplant. Evidence from competitive transplant assays shows that these defects are HSC intrinsic. NFAT5-deficient HSCs exhibit enhanced expression of type 1 interferon (IFN-1) response genes after transplant, and suppressing IFN-1 receptor prevents their exacerbated differentiation and cell death after reconstitution and improves long-term regeneration potential. Blockade of IFN-1 receptor also prevented the overdifferentiation of NFAT5-deficient HSCs after bone marrow ablation. These findings show that long-term IFN-1 responses to different hematopoietic stressors drive HSCs toward more differentiated progenitors, and that NFAT5 has an HSC-intrinsic role, limiting IFN-1 responses to preserve reconstitution potential. Our identification of cell-intrinsic mechanisms that strengthen the resistance of HSCs to stress could help to devise approaches to protect long-term stemness during the treatment of hematopoietic malignancies. (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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