中科院研究造血干细胞自我更新机制获进展

上一篇 / 下一篇  2011-08-26 11:13:19

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中国科学上海生命科学研究院/上海交通大学医学院健康科学研究所,中国科学院干细胞生物学重点实验室发育与疾病研究组于近日在国际著名学术期刊《血液》(Blood)在线发表了最新研究成果“Dominant-Negative C/ebpα and Polycomb Group Protein Bmi1 Extends Short-Lived Hematopoietic Stem/ProgenitorCells Lifespan and Induces Lethal Dyserythropoiesis”。该项研究利用斑马鱼这一模式生物,研究了造血发育和白血病发生过程中的关键调控因子C/ebpα和Bmi1在早期造血干/祖细胞生存和自我更新能力维持方面的作用,并建立了造血发育异常的斑马鱼疾病模型。该项成果为了解造血干细胞自我更新的分子调控路径,并进一步探索造血系统发育和疾病发生的机制提供了新的依据。

该研究组博士研究生周婷同学在刘廷析研究员的指导下,利用早期造血组织特异性的lmo2启动子和Cre-loxP系统,在斑马鱼早期造血干/祖细胞(primitive hematopoietic stem/progenitor cells)中特异性地表达白血病关键因子C/ebpα的显性负蛋白和Bmi1蛋白。发现显性负的C/ebpα蛋白(Dominant-Negative C/ebpα)可以使这群自我更新能力有限的短程干细胞(short-lived stem cells)的细胞寿命延长至胚胎定向造血(definitive hematopoiesis)阶段,并进而诱发红系造血异常(erythropoietic dysplasia)。进一步研究证实:C/ebpα蛋白可通过结合Bmi1基因启动子区的C/EBP结合序列,使C/ebpα显性负转基因鱼系的Bmi1表达特异性上升;在斑马鱼早期造血干/祖细胞特异性过表达Bmi1可获得与C/ebpα显性负转基因鱼系非常相似的表型,反之则可以使该异常表型基本消失。这些结果提示:表观遗传学调控因子Bmi1可能是C/ebpα蛋白的直接下游,显性负的C/ebpα蛋白正是通过上调Bmi1影响早期造血干/祖细胞的生存及自我更新能力。

该工作得到国家科技部、国家自然科学基金委、上海市科委、中国科学院以及上海市教委E-研究院的经费支持。

PMC:
PMID:

Dominant-negative C/ebpα and polycomb group protein Bmi1 extends short-lived hematopoietic stem/progenitor cells lifespan and induces lethal dyserythropoiesis

Ting Zhou, Lei Wang, Kang-Yong Zhu, Mei Dong, Peng-Fei Xu, Yi Chen, Sai-Juan Chen, Zhu Chen, Min Deng, and Ting Xi Liu

The primitive hematopoietic stem/progenitor cells (HSPCs) during embryonic hematopoiesis are believed to be short-lived (SL) with limited self-renewal potential. The fate and consequence of these short-lived HSPCs, once reprogrammed into "long-lived" in a living animal body, remain unknown. Here we show that targeted expression of a dominant-negative C/ebpα (C/ebpαDN) in the primitive SL-HSPCs during zebrafish embryogenesis extends their lifespan, allowing them to survive to later developmental stage to colonize the definitive hematopoietic sites, where they undergo a proliferative expansion followed by erythropoietic dysplasia and embryonic lethality due to circulation congestion. Mechanistically, C/ebpαDN binds to a conserved C/EBP-binding motif in the promoter region of bmi1 gene, associated with a specific induction of bmi1 transcription in the transgenic embryos expressing C/ebpαDN. Targeted expression of Bmi1 in the SL-HSPCs recapitulates nearly all aberrantphenotypes induced by C/ebpαDN, while knockdown of bmi1 largely rescues these abnormalities. The results indicate that Bmi1 acts immediate downstream of C/ebpαDN to regulate the survival and self-renewal of HSPCs and contribute to the erythropoietic dysplasia.


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