Catecholaminergic neurotransmitters regulate migration and repopulation of immature human CD34+ cells through Wnt signaling

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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 β2-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+Lin 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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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

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.

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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