2015 DEPARTMENT OF MEDICINE RESEARCH DAY
Title of Poster: DKK1 regulates hematopoietic stem cell regeneration
Presenter: Heather Himburg Ph.D.
Division: Hematology/Oncology
☒Faculty ☐Fellow ☐Resident ☐Post-doc Research Fellow ☐Graduate Student ☐Medical Student ☐Other
Principal Investigator/Mentor: Chute, John
Co-Investigators:
Thematic Poster Category: Development, Morphogenesis, Cell Growth and Differentiation, Apoptosis, Stem Cell Biology,
Carcinogenesis and Cancer Biology
Abstract
Dkk1 regulates hematopoietic stem cell regeneration
Heather A. Himburg 1, Phuong L. Doan 2, Xiao Yan
Chao2, Jeffrey Harris 4, John P. Chute 1,5,6 1
1,3
, Mamle Quarmyne
1,3
, Liman Zhao1, Evelyn Tran1, Nelson J.
Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, CA; 2 Division of Hematologic
Malignancies and Cellular Therapy, Duke University, Durham, NC; 3 Department of Pharmacology and Cancer
Biology, Duke University; 4 Celgene, Summit, New Jersey; 5 Broad Center for Regenerative Medicine and Stem Cell
Research, UCLA; 6 Jonsson Comprehensive Cancer Center, UCLA
Bone marrow endothelial cells (BM ECs) have been shown to regulate HSC regeneration following
myelosuppression. The role of osteolineage cells in regulating HSC regeneration remains less well
understood. Here, we show that deletion of the pro-apoptotic genes, Bak and Bax, in osterix (Osx)expressing osteoprogenitor cells promoted HSC regeneration and hematopoietic radioprotection of
mice following total body irradiation (TBI). We identified Dickkopf-1 (Dkk1) to be enriched in the BM
of radioprotected OsxCre;Bak1-/-;BaxFL/- mice and found that Bak/Bax-deficient osteolineage cells
expressed increased levels of Dkk1 compared to Bax-expressing osteolineage cells (p=0.0031).
Treatment of irradiated BM HSCs with DKK1 in vitro significantly increased the recovery of phenotypic
HSCs (p=0.0002), colony forming cells (CFCs)(p=0.003) and long-term repopulating HSCs compared
to control cultures (p=0.009). Systemic administration of Dkk1 to lethally irradiated C57Bl6 mice
accelerated the recovery of mature blood counts (p=0.008), BM HSCs (p=0.008) and progenitor cells
(p=0.007). Furthermore, survival after lethal irradiation was markedly increased in Dkk1 treated mice
(93%) compared to saline controls (27%; p=0.0004). Conversely, systemic administration of antiDkk1 antibody significantly delayed recovery of BM HSCs (p=0.002), peripheral white blood cells
(p=0.0004), neutrophils (p<0.0001) and lymphocytes (p=0.002) in irradiated mice compared to
irradiated, control mice. Dkk1 promoted HSC regeneration via suppression of reactive oxygen species
(ROS) and inhibition of caspase activation in HSCs following irradiation. Dkk1 represents a novel,
osteoprogenitor cell-derived paracrine factor which is necessary for normal hematopoietic regeneration
following irradiation and can be therapeutically delivered to accelerate hematopoietic reconstitution.