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⇱ Catecholaminergic neurotransmitters regulate migration and repopulation of immature human CD34+ cells through Wnt signaling | Nature Immunology

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Abstract

Catecholamines are important regulators of homeostasis, yet their functions in hematopoiesis are poorly understood. Here we report that immature human CD34+ cells dynamically expressed dopamine and Ξ²2-adrenergic receptors, with higher expression in the primitive CD34+CD38lo population. The myeloid cytokines G-CSF and GM-CSF upregulated neuronal receptor expression on immature CD34+ cells. Treatment with neurotransmitters increased the motility, proliferation and colony formation of human progenitor cells, correlating with increased polarity, expression of the metalloproteinase MT1-MMP and activity of the metalloproteinase MMP-2. Treatment with catecholamines enhanced human CD34+ cell engraftment of NOD-SCID mice through Wnt signaling activation and increased cell mobilization and bone marrow Sca-1+c-Kit+Linβˆ’ cell numbers. Our results identify new functions for neurotransmitters and myeloid cytokines in the direct regulation of human and mouse progenitor cell migration and development.

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Figure 1: Increased dopamine receptor expression in G-CSF-treated human CD34+ cells.
Figure 2: Dopamine receptor agonists increase the polarization and motility of CD34+ cells.
Figure 3: Dopamine receptor agonists increase the clonogenic progenitor content and engraftment potential of CD34+ cells.
Figure 4: Adrenergic neurotransmitters regulate CD34+ cell motility and proliferation.
Figure 5: Epinephrine induces progenitor cell proliferation, motility and in vivo mobilization.
Figure 6: Neurotransmitters activate the canonical Wnt signaling pathway.

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Acknowledgements

We thank L. Abel for assistance; E. Tzahor (Weizmann Institute of Science) for CRD-Frzb-enriched conditioned medium; and A. Globerson and S. Berrih-Aknin for discussions and critical review of the manuscript. Supported by Ares-Serono, the Gabriella Rich Center for Transplantation Biology, the Israel Science Foundation (796/04) and the Helen and Martin Kimmel Institute for Stem Cell Research at the Weizmann Institute of Science.

Author information

Authors and Affiliations

  1. Department of Immunology, The Weizmann Institute of Science, Rehovot, 76100, Israel

    Asaf Spiegel, Shoham Shivtiel, Alexander Kalinkovich, Aya Ludin, Neta Netzer, Polina Goichberg, Yaara Azaria & Tsvee Lapidot

  2. Department of Bone Marrow Transplantation & Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel

    Igor Resnick

  3. Department of Hematology & Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, 52621, Israel

    Izhar Hardan & Arnon Nagler

  4. Assaf Haroffe Medical Center, Tsrifin, 70300, Israel

    Herzel Ben-Hur

  5. Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, 76100, Israel

    Menachem Rubinstein

Authors
  1. Asaf Spiegel
  2. Shoham Shivtiel
  3. Alexander Kalinkovich
  4. Aya Ludin
  5. Neta Netzer
  6. Polina Goichberg
  7. Yaara Azaria
  8. Igor Resnick
  9. Izhar Hardan
  10. Herzel Ben-Hur
  11. Arnon Nagler
  12. Menachem Rubinstein
  13. Tsvee Lapidot

Contributions

A.S. designed and did experiments, analyzed data and wrote the manuscript; S.S., A.K., A.L., N.N., Y.A. and P.G. did experiments and analyzed data; I.R., I.H., H.B.-H. and A.N. provided human blood and bone marrow cells; M.R. provided advice on experimental design and manuscript preparation; and T.L. designed the research and wrote the manuscript.

Corresponding author

Correspondence to Tsvee Lapidot.

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Competing interests

Funding for this study was provided by Serono, and a patent is being filed on the basis of some of the results.

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Spiegel, A., Shivtiel, S., Kalinkovich, A. et al. Catecholaminergic neurotransmitters regulate migration and repopulation of immature human CD34+ cells through Wnt signaling. Nat Immunol 8, 1123–1131 (2007). https://doi.org/10.1038/ni1509

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  • DOI: https://doi.org/10.1038/ni1509

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