CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation.

Autor:	Lawson H; Laboratory of Haematopoietic Stem Cell & Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK; Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK., van de Lagemaat LN; Laboratory of Haematopoietic Stem Cell & Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK; Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK., Barile M; Department of Haematology, Wellcome and Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0AW, UK., Tavosanis A; Laboratory of Haematopoietic Stem Cell & Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK., Durko J; Laboratory of Haematopoietic Stem Cell & Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK., Villacreces A; Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK., Bellani A; Laboratory of Haematopoietic Stem Cell & Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK., Mapperley C; Laboratory of Haematopoietic Stem Cell & Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK., Georges E; Laboratory of Haematopoietic Stem Cell & Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK., Martins-Costa C; Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK., Sepulveda C; Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK., Allen L; Laboratory of Haematopoietic Stem Cell & Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK., Campos J; Laboratory of Haematopoietic Stem Cell & Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK., Campbell KJ; CRUK Beatson Institute, Glasgow, UK., O'Carroll D; Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK., Göttgens B; Department of Haematology, Wellcome and Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0AW, UK., Cory S; The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia., Rodrigues NP; European Cancer Stem Cell Research Institute, Cardiff University, School of Biosciences, Cardiff CF24 4HQ, UK., Guitart AV; Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK; Université de Bordeaux, Institut National de la Santé et de la Recherche Médicale INSERM U1035, 33000 Bordeaux, France. Electronic address: amelie.guitart@u-bordeaux.fr., Kranc KR; Laboratory of Haematopoietic Stem Cell & Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK. Electronic address: kamil.kranc@qmul.ac.uk.
Jazyk:	angličtina
Zdroj:	Stem cell reports [Stem Cell Reports] 2021 Nov 09; Vol. 16 (11), pp. 2784-2797. Date of Electronic Publication: 2021 Oct 28.
DOI:	10.1016/j.stemcr.2021.10.001
Abstrakt:	Hematopoietic stem cells (HSCs) reside at the apex of the hematopoietic differentiation hierarchy and sustain multilineage hematopoiesis. Here, we show that the transcriptional regulator CITED2 is essential for life-long HSC maintenance. While hematopoietic-specific Cited2 deletion has a minor impact on steady-state hematopoiesis, Cited2-deficient HSCs are severely depleted in young mice and fail to expand upon aging. Moreover, although they home normally to the bone marrow, they fail to reconstitute hematopoiesis upon transplantation. Mechanistically, CITED2 is required for expression of key HSC regulators, including GATA2, MCL-1, and PTEN. Hematopoietic-specific expression of anti-apoptotic MCL-1 partially rescues the Cited2-deficient HSC pool and restores their reconstitution potential. To interrogate the Cited2→Pten pathway in HSCs, we generated Cited2;Pten compound heterozygous mice, which had a decreased number of HSCs that failed to reconstitute the HSC compartment. In addition, CITED2 represses multiple pathways whose elevated activity causes HSC exhaustion. Thus, CITED2 promotes pathways necessary for HSC maintenance and suppresses those detrimental to HSC integrity. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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