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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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.
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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