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

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 impac...

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Autores principales: 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, Dónal, Göttgens, Berthold, Cory, Suzanne, Rodrigues, Neil P., Guitart, Amelie V., Kranc, Kamil R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581166/
https://www.ncbi.nlm.nih.gov/pubmed/34715054
http://dx.doi.org/10.1016/j.stemcr.2021.10.001
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author 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, Dónal
Göttgens, Berthold
Cory, Suzanne
Rodrigues, Neil P.
Guitart, Amelie V.
Kranc, Kamil R.
author_facet 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, Dónal
Göttgens, Berthold
Cory, Suzanne
Rodrigues, Neil P.
Guitart, Amelie V.
Kranc, Kamil R.
author_sort Lawson, Hannah
collection PubMed
description 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.
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spelling pubmed-85811662021-11-18 CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis 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, Dónal Göttgens, Berthold Cory, Suzanne Rodrigues, Neil P. Guitart, Amelie V. Kranc, Kamil R. Stem Cell Reports Article 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. Elsevier 2021-10-28 /pmc/articles/PMC8581166/ /pubmed/34715054 http://dx.doi.org/10.1016/j.stemcr.2021.10.001 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
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, Dónal
Göttgens, Berthold
Cory, Suzanne
Rodrigues, Neil P.
Guitart, Amelie V.
Kranc, Kamil R.
CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation
title CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation
title_full CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation
title_fullStr CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation
title_full_unstemmed CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation
title_short CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation
title_sort cited2 coordinates key hematopoietic regulatory pathways to maintain the hsc pool in both steady-state hematopoiesis and transplantation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581166/
https://www.ncbi.nlm.nih.gov/pubmed/34715054
http://dx.doi.org/10.1016/j.stemcr.2021.10.001
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