中科院研究造血干细胞自我更新机制获进展

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 aberrant phenotypes 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.