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Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms. Nat Med 2017 01;23(1):91-99

Date

12/06/2016

Pubmed ID

27918563

Pubmed Central ID

PMC5592969

DOI

10.1038/nm.4251

Scopus ID

2-s2.0-85001889482   45 Citations

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.

Author List

Himburg HA, Doan PL, Quarmyne M, Yan X, Sasine J, Zhao L, Hancock GV, Kan J, Pohl KA, Tran E, Chao NJ, Harris JR, Chute JP

Author

Heather A. Himburg PhD Associate Professor in the Radiation Oncology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Bone Marrow
Bone Marrow Cells
Cell Self Renewal
Cytokines
Endothelial Cells
Enzyme-Linked Immunosorbent Assay
Epidermal Growth Factor
ErbB Receptors
Flow Cytometry
Gene Expression Profiling
Hematopoietic Stem Cells
Intercellular Signaling Peptides and Proteins
Mice
Mitochondria
Osteoblasts
Radiation Injuries, Experimental
Reactive Oxygen Species
Regeneration
Sp7 Transcription Factor
Transcription Factors
Whole-Body Irradiation
bcl-2 Homologous Antagonist-Killer Protein
bcl-2-Associated X Protein