Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms

• Published in: Nature medicine Vol. 23; no. 1; pp. 91 - 99
• Main Authors: Himburg, Heather A, Doan, Phuong L, Quarmyne, Mamle, Yan, Xiao, Sasine, Joshua, Zhao, Liman, Hancock, Grace V, Kan, Jenny, Pohl, Katherine A, Tran, Evelyn, Chao, Nelson J, Harris, Jeffrey R, Chute, John P
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2017; Nature Publishing Group
• Subjects: 631/532/1542; 692/308/575; Animals; Apoptosis; BAX protein; bcl-2 Homologous Antagonist-Killer Protein - genetics; bcl-2-Associated X Protein - genetics; Biocompatibility; Biomedical materials; Biomedicine; Bone marrow; Bone Marrow - metabolism; Bone Marrow Cells - metabolism; Cancer Research; Cell Self Renewal; Cells (biology); Cellular proteins; Clonal deletion; Crosstalk; Cytokines - metabolism; Data recovery; Dkk1 protein; Endothelial cells; Endothelial Cells - metabolism; Enzyme-Linked Immunosorbent Assay; Epidermal growth factor; Epidermal Growth Factor - secretion; Flow Cytometry; Gene Expression Profiling; Genetic aspects; Growth factors; Health aspects; Hematopoietic stem cells; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - radiation effects; Infectious Diseases; Intercellular Signaling Peptides and Proteins - metabolism; Intercellular Signaling Peptides and Proteins - pharmacology; Irradiation; Metabolic Diseases; Mice; Mitochondria; Mitochondria - metabolism; Molecular Medicine; Myelosuppression; Neurosciences; Osteoblasts - metabolism; Paracrine signalling; Progenitor cells; Proteins; Radiation; Radiation Injuries, Experimental; Radiation protection; Reactive Oxygen Species; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Regeneration; Regeneration (Biology); Rodents; Secretion; Senescence; Sp7 Transcription Factor; Stem cells; Transcription Factors - metabolism; Whole-Body Irradiation
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.4251

The Wnt pathway inhibitor Dkk1, which is produced by bone marrow osteolineage cells, promotes hematopoietic recovery after radiation injury by both direct effects on hematopoietic cells and indirect effects on bone marrow endothelial cells. 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.