Apc regulates the function of hematopoietic stem cells largely through β-catenin-dependent mechanisms
Apc regulates the function of hematopoietic stem cells largely through β-catenin-dependent mechanisms
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DOI：
10.1182/blood-2012-12-473470
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发表时间：
2013-05-16
期刊：
影响因子：
20.3
通讯作者：
Qian, Zhijian
中科院分区：
文献类型：
--
作者：
Li, Wenshu;Hou, Yu;Qian, Zhijian
新出现的证据表明，腺瘤性结肠息肉病（APC）在维持造血干/祖细胞（HSC/HPC）中起着关键作用。Apc在HSCs/HPCs中发挥作用的分子途径尚不清楚。通过遗传学方法，我们证明了β-连环蛋白的失活挽救了APC缺陷型HSC/HPC的衰竭，从而防止了APC缺陷型小鼠的骨髓衰竭。β-连环蛋白缺失抑制Apc缺陷型HSC/HPC的过度增殖和凋亡，以及它们在髓系和红系分化中的缺陷。此外，β-连环蛋白的缺失逆转了Lin（-）Sca（+）c-Kit（+）中Apc消融诱导的Cdkn 1a、Cdkn 1b和Mcl 1的下调。在长期干细胞功能的测定中，与β-连环蛋白缺陷和对照HSC相比，Apc和β-连环蛋白缺陷的HSC显示出显著增强的自我更新能力。我们的研究结果表明，Apc调节的生存，增殖和分化的HSC/HPC主要通过β-连环蛋白介导的途径。他们还表明，包括β-连环蛋白在内的Apc的多个下游靶点可能协同调节HSC自我更新。
Emerging evidence suggests that adenomatous polyposis coli (Apc) plays a critical role in the maintenance of hematopoietic stem/progenitor cells (HSCs/HPCs). The molecular pathways responsible for the function of Apc in HSCs/HPCs remain unclear. By genetic approach, we demonstrated that inactivation of beta-catenin rescued the exhaustion of Apc-deficient HSCs/HPCs, thereby preventing bone marrow failure in Apc-deficient mice. beta-catenin loss inhibited the excessive proliferation and apoptosis of Apcdeficient HSCs/HPCs, as well as their defects in myeloid and erythroid differentiation. In addition, loss of beta-catenin reversed the down-regulation of Cdkn1a, Cdkn1b, and Mcl1 induced by Apc ablation in Lin(-)Sca(+)c-Kit(+). In assays of long-term stem cell function, the HSCs with deficiency of both Apc and beta-catenin displayed a significantly enhanced self-renewal capacity compared with beta-catenin-deficient and control HSCs. Our findings suggest that Apc regulates the survival, proliferation, and differentiation of HSCs/HPCs largely through a beta-catenin-mediated pathway. They also indicate that multiple downstream targets of Apc including beta-catenin may coordinately regulate HSC self-renewal.