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

Publication ,  Journal Article
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
Published in: Nat Med
January 2017

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.

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Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

January 2017

Volume

23

Issue

1

Start / End Page

91 / 99

Location

United States

Related Subject Headings

  • bcl-2-Associated X Protein
  • bcl-2 Homologous Antagonist-Killer Protein
  • Whole-Body Irradiation
  • Transcription Factors
  • Sp7 Transcription Factor
  • Regeneration
  • Reactive Oxygen Species
  • Radiation Injuries, Experimental
  • Osteoblasts
  • Mitochondria
 

Citation

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Himburg, H. A., Doan, P. L., Quarmyne, M., Yan, X., Sasine, J., Zhao, L., … Chute, J. P. (2017). Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms. Nat Med, 23(1), 91–99. https://doi.org/10.1038/nm.4251
Himburg, Heather A., Phuong L. Doan, Mamle Quarmyne, Xiao Yan, Joshua Sasine, Liman Zhao, Grace V. Hancock, et al. “Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms.Nat Med 23, no. 1 (January 2017): 91–99. https://doi.org/10.1038/nm.4251.
Himburg HA, Doan PL, Quarmyne M, Yan X, Sasine J, Zhao L, et al. Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms. Nat Med. 2017 Jan;23(1):91–9.
Himburg, Heather A., et al. “Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms.Nat Med, vol. 23, no. 1, Jan. 2017, pp. 91–99. Pubmed, doi:10.1038/nm.4251.
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. Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms. Nat Med. 2017 Jan;23(1):91–99.

Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

January 2017

Volume

23

Issue

1

Start / End Page

91 / 99

Location

United States

Related Subject Headings

  • bcl-2-Associated X Protein
  • bcl-2 Homologous Antagonist-Killer Protein
  • Whole-Body Irradiation
  • Transcription Factors
  • Sp7 Transcription Factor
  • Regeneration
  • Reactive Oxygen Species
  • Radiation Injuries, Experimental
  • Osteoblasts
  • Mitochondria