title: Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms.
abstract: The role of osteolineage cells in regulating hematopoietic stem cell (HSC) regeneration following myelosuppression is not well understood. Here we show that deletion of the pro-apoptotic genes Bak and Bax in osterix (Osx, also known as Sp7 transcription factor 7)-expressing cells in mice promotes HSC regeneration and hematopoietic radioprotection following total body irradiation. These mice showed increased bone marrow (BM) levels of the protein dickkopf-1 (Dkk1), which was produced in Osx-expressing BM cells. Treatment of irradiated HSCs with Dkk1 in vitro increased the recovery of both long-term repopulating HSCs and progenitor cells, and systemic administration of Dkk1 to irradiated mice increased hematopoietic recovery and improved survival. Conversely, inducible deletion of one allele of Dkk1 in Osx-expressing cells in adult mice inhibited the recovery of BM stem and progenitor cells and of complete blood counts following irradiation. Dkk1 promoted hematopoietic regeneration via both direct effects on HSCs, in which treatment with Dkk1 decreased the levels of mitochondrial reactive oxygen species and suppressed senescence, and indirect effects on BM endothelial cells, in which treatment with Dkk1 induced epidermal growth factor (EGF) secretion. Accordingly, blockade of the EGF receptor partially abrogated Dkk1-mediated hematopoietic recovery. These data identify Dkk1 as a regulator of hematopoietic regeneration and demonstrate paracrine cross-talk between BM osteolineage cells and endothelial cells in regulating hematopoietic reconstitution following injury.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Himburg
authors.affiliation: Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, North Carolina, USA.
authors.forename: Phuong L
authors.initials: PL
authors.lastname: Doan
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA.|Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA.
authors.forename: Mamle
authors.initials: M
authors.lastname: Quarmyne
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA.|Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yan
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Sasine
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA.
authors.forename: Liman
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Grace V
authors.initials: GV
authors.lastname: Hancock
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Kan
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Pohl
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Tran
authors.affiliation: Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, North Carolina, USA.
authors.forename: Nelson J
authors.initials: NJ
authors.lastname: Chao
authors.affiliation: Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, North Carolina, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Harris
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA.|Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, California, USA.|Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Chute
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism*; D000066673:Cell Self Renewal; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism*; D011833:Radiation Injuries, Experimental; D017382:Reactive Oxygen Species; D012038:Regeneration; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000378:metabolism*; D014916:Whole-Body Irradiation; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D016207:Cytokines; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D004815:Epidermal Growth Factor; D066246:ErbB Receptors