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

Hannah Lawson; Louie N van de Lagemaat; Melania Barile; Andrea Tavosanis; Jozef Durko; Arnaud Villacreces; Aarushi Bellani; Christopher Mapperley; Elise Georges; Catarina Martins-Costa; Catarina Sepulveda; Lewis Allen; Joana Campos; Kirsteen J Campbell; Dónal O'Carroll; Berthold Göttgens; Suzanne Cory; Neil P Rodrigues; Amelie V Guitart; Kamil R Kranc

doi:10.1016/j.stemcr.2021.10.001

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

Hannah Lawson, Louie N van de Lagemaat, Melania Barile, Andrea Tavosanis, Jozef Durko, Arnaud Villacreces, Aarushi Bellani, Christopher Mapperley, Elise Georges, Catarina Martins-Costa, Catarina Sepulveda, Lewis Allen, Joana Campos, Kirsteen J Campbell, Dónal O'Carroll, Berthold Göttgens, Suzanne Cory, Neil P Rodrigues, Amelie V Guitart^* (Corresponding Author), Kamil R Kranc^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

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.

Original language	English
Pages (from-to)	2784-2797
Number of pages	14
Journal	Stem Cell Reports
Volume	16
Issue number	11
Early online date	9 Nov 2021
DOIs	https://doi.org/10.1016/j.stemcr.2021.10.001
Publication status	Published - 9 Nov 2021
Externally published	Yes

Bibliographical note

This research was funded by Cancer Research UK (CRUK) Senior Cancer Research Fellowship and a CRUK Program Grant awarded to K.R.K. (C29967/A14633 and C29967/A26787). K.R.K.'s laboratory is also supported by grants from The Barts Charity, The Kay Kendall Leukaemia Fund and Blood Cancer UK. A.V.G. is supported by Ligue contre le cancer. This research was also funded in part by the Wellcome (203151/Z/16/Z) and the Medical Research Council (MC_PC_17230). We thank Vladimir Benes and Jelena Pistolic (Genomics Core Facility, EMBL, Heidelberg) for performing RNA-seq.

Data Availability Statement

The RNA-seq data are deposited in NCBI's Gene Expression Omnibus (accession no. GSE175372).

Supplemental information can be found online at https://doi.org/
10.1016/j.stemcr.2021.10.001.

Keywords

hematopoietic stem cell
CITED2
MCL-1
PTEN
hematopoiesis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Lawson, H., van de Lagemaat, L. N., Barile, M., Tavosanis, A., Durko, J., Villacreces, A., Bellani, A., Mapperley, C., Georges, E., Martins-Costa, C., Sepulveda, C., Allen, L., Campos, J., Campbell, K. J., O'Carroll, D., Göttgens, B., Cory, S., Rodrigues, N. P., Guitart, A. V., & Kranc, K. R. (2021). CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation. Stem Cell Reports, 16(11), 2784-2797. https://doi.org/10.1016/j.stemcr.2021.10.001

Lawson, H, van de Lagemaat, LN, Barile, M, Tavosanis, A, Durko, J, Villacreces, A, Bellani, A, Mapperley, C, Georges, E, Martins-Costa, C, Sepulveda, C, Allen, L, Campos, J, Campbell, KJ, O'Carroll, D, Göttgens, B, Cory, S, Rodrigues, NP, Guitart, AV & Kranc, KR 2021, 'CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation', Stem Cell Reports, vol. 16, no. 11, pp. 2784-2797. https://doi.org/10.1016/j.stemcr.2021.10.001

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

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.",

keywords = "hematopoietic stem cell, CITED2, MCL-1, PTEN, hematopoiesis",

author = "Hannah Lawson and {van de Lagemaat}, {Louie N} and Melania Barile and Andrea Tavosanis and Jozef Durko and Arnaud Villacreces and Aarushi Bellani and Christopher Mapperley and Elise Georges and Catarina Martins-Costa and Catarina Sepulveda and Lewis Allen and Joana Campos and Campbell, {Kirsteen J} and D{\'o}nal O'Carroll and Berthold G{\"o}ttgens and Suzanne Cory and Rodrigues, {Neil P} and Guitart, {Amelie V} and Kranc, {Kamil R}",

note = "This research was funded by Cancer Research UK (CRUK) Senior Cancer Research Fellowship and a CRUK Program Grant awarded to K.R.K. (C29967/A14633 and C29967/A26787). K.R.K.'s laboratory is also supported by grants from The Barts Charity, The Kay Kendall Leukaemia Fund and Blood Cancer UK. A.V.G. is supported by Ligue contre le cancer. This research was also funded in part by the Wellcome (203151/Z/16/Z) and the Medical Research Council (MC_PC_17230). We thank Vladimir Benes and Jelena Pistolic (Genomics Core Facility, EMBL, Heidelberg) for performing RNA-seq.",

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T1 - CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation

AU - Lawson, Hannah

AU - van de Lagemaat, Louie N

AU - Barile, Melania

AU - Tavosanis, Andrea

AU - Durko, Jozef

AU - Villacreces, Arnaud

AU - Bellani, Aarushi

AU - Mapperley, Christopher

AU - Georges, Elise

AU - Martins-Costa, Catarina

AU - Sepulveda, Catarina

AU - Allen, Lewis

AU - Campos, Joana

AU - Campbell, Kirsteen J

AU - O'Carroll, Dónal

AU - Göttgens, Berthold

AU - Cory, Suzanne

AU - Rodrigues, Neil P

AU - Guitart, Amelie V

AU - Kranc, Kamil R

N1 - This research was funded by Cancer Research UK (CRUK) Senior Cancer Research Fellowship and a CRUK Program Grant awarded to K.R.K. (C29967/A14633 and C29967/A26787). K.R.K.'s laboratory is also supported by grants from The Barts Charity, The Kay Kendall Leukaemia Fund and Blood Cancer UK. A.V.G. is supported by Ligue contre le cancer. This research was also funded in part by the Wellcome (203151/Z/16/Z) and the Medical Research Council (MC_PC_17230). We thank Vladimir Benes and Jelena Pistolic (Genomics Core Facility, EMBL, Heidelberg) for performing RNA-seq.

PY - 2021/11/9

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N2 - 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.

AB - 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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KW - CITED2

KW - MCL-1

KW - PTEN

KW - hematopoiesis

U2 - 10.1016/j.stemcr.2021.10.001

DO - 10.1016/j.stemcr.2021.10.001

M3 - Article

C2 - 34715054

SN - 2213-6711

VL - 16

SP - 2784

EP - 2797

JO - Stem Cell Reports

JF - Stem Cell Reports

IS - 11

ER -

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

Abstract

Bibliographical note

Data Availability Statement

Keywords

UN SDGs

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