Deletion of the Imprinted Gene Grb10 Promotes Hematopoietic Stem Cell Self-Renewal and Regeneration

作者：Yan Xiao; Himburg Heather A; Pohl Katherine; Quarmyne Mamle; Tran Evelyn; Zhang Yurun; Fang Tiancheng; Kan Jenny; Chao Nelson J; Zhao Liman; Doan Phuong L; Chute John P

来源：Cell Reports, 2016, 17(6): 1584-1594.

DOI：10.1016/j.celrep.2016.10.025

Imprinted genes are differentially expressed by adult stem cells, but their functions in regulating adult stem cell fate are incompletely understood. Here we show that growth factor receptor-bound protein 10 (Grb10), an imprinted gene, regulates hematopoietic stem cell (HSC) self-renewal and regeneration. Deletion of the maternal allele of Grb10 in mice (Grb10(m/+) mice) substantially increased HSC long-term repopulating capacity, as compared to that of Grb10(+/+) mice. After total body irradiation (TBI), Grb10(m/+) mice demonstrated accelerated HSC regeneration and hematopoietic reconstitution, as compared to Grb10(+/+) mice. Grb10-deficient HSCs displayed increased proliferation after competitive transplantation or TBI, commensurate with upregulation of CDK4 and Cyclin E. Furthermore, the enhanced HSC regeneration observed in Grb10-deficient mice was dependent on activation of the Akt/mTORC1 pathway. This study reveals a function for the imprinted gene Grb10 in regulating HSC self-renewal and regeneration and suggests that the inhibition of Grb10 can promote hematopoietic regeneration in vivo.

• 出版日期2016-11-1