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

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  • dc.contributor.author Traveset Martínez, Laia
  • dc.contributor.author Cerdán Porqueras, Víctor
  • dc.contributor.author Huerga Encabo, Hector, 1989-
  • dc.contributor.author Avalle, Silvia
  • dc.contributor.author Esteve-Codina, Anna
  • dc.contributor.author Fornas Carreño, Oscar
  • dc.contributor.author Aramburu, José (Aramburu Beltrán)
  • dc.contributor.author López Rodríguez, M. Cristina
  • dc.date.accessioned 2024-11-18T14:57:00Z
  • dc.date.available 2024-11-18T14:57:00Z
  • dc.date.issued 2024
  • dc.description.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.
  • dc.description.sponsorship This work was supported by the Spanish Ministry of Science and Innovation and European Fund for Regional Development (FEDER) (RTI2018-095902-B-I00 and PID2021-128721OB-I00), Fundació la Marató de TV3 (201619-30), and the Worldwide Cancer Research United Kingdom Foundation (grant 20-0144). A.E.-C. was funded by ISCIII/MINECO (PT17/0009/0019) and cofunded by FEDER. Research in the laboratory of C.L.-R. and J.A. was also supported by the Generalitat de Catalunya (2021SGR00683) and the Spanish Ministry of Science Innovation through the “Unidad de Excelencia María de Maeztu” program funded by the Agencia Estatal de Investigación (MDM-2014-0370 and CEX2018-000792-M). L.T. was funded by a predoctoral contract (BES-2015-074170) associated to MDM-2014-0370. V.C.P. and H.H.E. were funded by the program Formación de Profesorado Universitario of Ministerio de Universidades (FPU19-04119 to V.C.P., and FPU13/01798 to H.H.E.). Additional funding to C.L.-R. is from the ICREA Acadèmia 2014 and 2022 awards of Institució Catalana de Recerca i Estudis Avançats (ICREA, Generalitat de Catalunya).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Traveset L, Cerdán Porqueras V, Huerga Encabo H, Avalle S, Esteve-Codina A, Fornas O, et al. NFAT5 counters long-term IFN-1 responses in hematopoietic stem cells to preserve reconstitution potential. Blood Adv. 2024 Nov 12;8(21):5510-26. DOI: 10.1182/bloodadvances.2023011306
  • dc.identifier.doi http://dx.doi.org/10.1182/bloodadvances.2023011306
  • dc.identifier.issn 2473-9529
  • dc.identifier.uri http://hdl.handle.net/10230/68727
  • dc.language.iso eng
  • dc.publisher American Society of Hematology
  • dc.relation.ispartof Blood Adv. 2024 Nov 12;8(21):5510-26
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-095902-B-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-128721OB-I00
  • dc.rights © 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. http://creativecommons.org/licenses/by-nc-nd/4.0/
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
  • dc.subject.keyword Hematopoiesis and Stem Cells
  • dc.subject.keyword Transplantation
  • dc.title NFAT5 counters long-term IFN-1 responses in hematopoietic stem cells to preserve reconstitution potential
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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