CITED2 coordinates key haematopoietic regulatory pathways to maintain the HSC pool in both steady-state haematopoiesis and transplantation

Lawson, Hannah, van de Lagemaat, Louie N., Barile, Melania, Tavosanis, Andrea, Durko, Jozef, Villacreces, Arnaud, Bellani, Aarushi, Mapperley, Christopher, Georges, Elise, Martins-Costa, Catarina, Sepulveda, Catarina, Allen, Lewis, Campos, Joana, Campbell, Kirsteen J., O'Carroll, Donal, Gottgens, Berthold, Cory, Suzanne, Rodrigues, Neil P. ORCID: https://orcid.org/0000-0002-1925-7733, Guitart, Amelie V. and Kranc, Kamil R. 2021. CITED2 coordinates key haematopoietic regulatory pathways to maintain the HSC pool in both steady-state haematopoiesis and transplantation. Stem Cell Reports 16 (11) , pp. 2784-2797. 10.1016/j.stemcr.2021.10.001

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
Additional Information:	This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Publisher:	Cell Press
ISSN:	2213-6711
Date of First Compliant Deposit:	4 October 2021
Date of Acceptance:	1 October 2021
Last Modified:	03 May 2023 19:01
URI:	https://orca.cardiff.ac.uk/id/eprint/144622

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