Unknown

Dataset Information

0

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


ABSTRACT: Summary 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. Highlights • Unperturbed hematopoiesis can be sustained long term while the HSC pool is depleted• CITED2 promotes HSC survival but not quiescence under homeostatic conditions• CITED2 maintains the HSC pool by controlling Mcl1 and Pten expression Kranc, Guitart, and colleagues demonstrate that Cited2 deletion causes a progressive HSC loss under steady-state conditions without perturbing normal hematopoiesis. The authors show that CITED2 maintains HSCs by regulating the expression of Mcl1 and Pten. Finally, they indicate that CITED2 promotes multiple pathways necessary for HSC maintenance and suppresses those detrimental to HSC integrity to coordinate HSC function.

SUBMITTER: Lawson H 

PROVIDER: S-EPMC8581166 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC8459380 | biostudies-literature
| S-EPMC5998934 | biostudies-literature
| S-EPMC3109710 | biostudies-literature
| S-EPMC2018670 | biostudies-literature
| S-EPMC6468739 | biostudies-literature
| S-EPMC4738301 | biostudies-literature
| S-EPMC2644141 | biostudies-literature
| S-EPMC4655130 | biostudies-literature
| S-EPMC2828538 | biostudies-literature
| S-EPMC4693298 | biostudies-literature