Deletion of the Imprinted Gene Grb10 Promotes Hematopoietic Stem Cell Self-Renewal and Regeneration.
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.
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.
Xiao
X
Yan
Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, CA 90095, USA.
Heather A
HA
Himburg
Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, CA 90095, USA.
Katherine
K
Pohl
Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, CA 90095, USA.
Mamle
M
Quarmyne
Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, CA 90095, USA.
Evelyn
E
Tran
Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA.
Yurun
Y
Zhang
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.
Tiancheng
T
Fang
Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, CA 90095, USA.
Jenny
J
Kan
Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, NC 27710, USA.
Nelson J
NJ
Chao
Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, CA 90095, USA.
Liman
L
Zhao
Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, NC 27710, USA.
Phuong L
PL
Doan
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.
John P
JP
Chute
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D049109:Cell Proliferation; D000066673:Cell Self Renewal / Q000235:genetics*; D051383:GRB10 Adaptor Protein / Q000172:deficiency* / Q000378:metabolism; D017353:Gene Deletion; D018392:Genomic Imprinting; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012038:Regeneration; D015398:Signal Transduction; D014916:Whole-Body Irradiation
C495959:Grb10 protein, mouse; D051383:GRB10 Adaptor Protein; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt
adaptor protein; hematopoietic stem cells; imprinted gene; regeneration; self-renewal