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Cell Rep. 2016 Nov 1;17(6):1584-1594. doi: 10.1016/j.celrep.2016.10.025.

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

Author information

1
Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA.
2
Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, CA 90095, USA.
3
Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA.
4
Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, NC 27710, USA.
5
Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA. Electronic address: jchute@mednet.ucla.edu.

Abstract

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 (Grb10m/+ mice) substantially increased HSC long-term repopulating capacity, as compared to that of Grb10+/+ mice. After total body irradiation (TBI), Grb10m/+ 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.

KEYWORDS:

adaptor protein; hematopoietic stem cells; imprinted gene; regeneration; self-renewal

PMID:
27806297
PMCID:
PMC5963255
DOI:
10.1016/j.celrep.2016.10.025
[Indexed for MEDLINE]
Free PMC Article

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