CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation.
CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation.
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DOI：
10.1016/j.stemcr.2021.10.001
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发表时间：
2021-11-09
影响因子：
5.9
通讯作者：
Kranc KR
中科院分区：
文献类型：
--
作者：
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
造血干细胞（hematopoieticstemcells，HSCs）位于造血分化层次的顶端，维持多系造血功能。在这里，我们表明，转录调节CITED 2是必不可少的终身HSC的维护。虽然造血特异性Cited 2缺失对稳态造血有轻微影响，但Cited 2缺陷型HSC在年轻小鼠中严重耗尽，并且在衰老时无法扩增。此外，尽管它们正常地回到骨髓，但它们在移植时不能重建造血。从机制上讲，CITED 2是关键HSC调节因子（包括GATA 2、MCL-1和PTEN）表达所必需的。抗凋亡MCL-1的造血特异性表达部分挽救了Cited 2缺陷的HSC池并恢复其重建潜力。为了研究HSC中的Cited 2 →Pten通路，我们产生了Cited 2;Pten复合杂合小鼠，其具有减少的HSC数量，其不能重建HSC区室。此外，CITED 2抑制多种途径，其活性升高导致HSC耗竭。因此，CITED 2促进HSC维持所必需的途径，并抑制那些对HSC完整性有害的途径。当HSC池耗尽时，未受干扰的造血可以长期维持，CITED 2促进HSC存活，但在稳态条件下不静止CITED 2通过控制Mcl 1和Pten表达维持HSC池，Kranc，Guitart及其同事证明，Cited 2缺失在稳态条件下导致HSC进行性损失，而不干扰正常造血。作者表明，CITED 2通过调节Mcl 1和Pten的表达来维持HSC。最后，他们表明CITED 2促进HSC维持所必需的多种途径，并抑制那些对HSC完整性有害的途径以协调HSC功能。
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. 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.
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DOI：
10.1084/jem.20160719
发表时间：
2017-07-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kim E;Cheng Y;Bolton-Gillespie E;Cai X;Ma C;Tarangelo A;Le L;Jambhekar M;Raman P;Hayer KE;Wertheim G;Speck NA;Tong W;Viatour P
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DOI：
10.1084/jem.20161087
发表时间：
2017-03-06
期刊：
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影响因子：
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Kranc KR
影响因子：
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