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

Nature Medicine volume 23, pages 91–99 (2017)Cite this article

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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.

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Figure 1: Deletion of Bak and Bax in Osx+ BM cells radioprotects hematopoietic stem and progenitor cells.
Figure 2: Dkk1 promotes hematopoietic regeneration in vitro and in vivo.
Figure 3: Inhibition or deficiency of Dkk1 in Osx-expressing BM cells suppresses hematopoietic regeneration.
Figure 4: Dkk1 suppresses HSC senescence following irradiation and induces EGF secretion by BM ECs.

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Acknowledgements

We thank S. Vainio (University of Oulu) for the Dkk1FL/+ mice. This work was supported, in part, by NHLBI grant HL-086998-05 (J.P.C.), NIAID grants AI-067769-11 (J.P.C.) and AI-107333 (J.P.C.), the California Institute for Regenerative Medicine Leadership Award LA1-08014 (J.P.C.) and the NIAID Centers for Medical Countermeasures Against Radiation (CMCR) Pilot Award 2U19AI067773-11 (H.A.H.).

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Author notes

  1. Heather A Himburg and Phuong L Doan: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA

    Heather A Himburg, Mamle Quarmyne, Xiao Yan, Joshua Sasine, Liman Zhao, Jenny Kan, Katherine A Pohl, Evelyn Tran & John P Chute

  2. Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, North Carolina, USA

    Phuong L Doan, Nelson J Chao & Jeffrey R Harris

  3. Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA

    Mamle Quarmyne & Xiao Yan

  4. Department of Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA.,

    Grace V Hancock

  5. Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, California, USA.,

    John P Chute

  6. Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California, USA.,

    John P Chute

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Contributions

J.P.C. conceived of and designed the study; H.A.H. designed and performed the majority of the experiments and analyzed data; P.L.D. and J.R.H. performed experiments and analyzed data; M.Q., X.Y., J.S., L.Z., G.V.H., J.K., K.A.P. and E.T. performed experiments; N.J.C. contributed to the design and interpretation of the study; and H.A.H. and J.P.C. wrote the paper.

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Correspondence to John P Chute.

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Himburg, H., Doan, P., Quarmyne, M. et al. Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms. Nat Med 23, 91–99 (2017). https://doi.org/10.1038/nm.4251

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