Pharmacological mobilization of hematopoietic stem progenitor cells (HSPCs) from bone marrow (BM) into peripheral blood (PB) is a result of mobilizing agent-induced “sterile inflammation” in the BM microenvironment due to complement cascade (ComC) activation. Here we provide evidence that ATP, as an extracellular nucleotide secreted in a pannexin-1-dependent manner from BM cells, triggers activation of the ComC and initiates the mobilization process. This process is augmented in a P2X7 receptor-dependent manner, and P2X7-KO mice are poor mobilizers. Furthermore, after its release into the extracellular space, ATP is processed by ectonucleotidases: CD39 converts ATP to AMP, and CD73 converts AMP to adenosine. We observed that CD73-deficient mice mobilize more HSPCs than do wild-type mice due to a decrease in adenosine concentration in the extracellular space, indicating a negative role for adenosine in the mobilization process. This finding has been confirmed by injecting mice with adenosine along with pro-mobilizing agents. In sum, we demonstrate for the first time that purinergic signaling involving ATP and its metabolite adenosine regulate the mobilization of HSPCs. Although ATP triggers and promotes this process, adenosine has an inhibitory effect. Thus, administration of ATP together with G-CSF or AMD3100 or inhibition of CD73 by small molecule antagonists may provide the basis for more efficient mobilization strategies.
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This work was supported by NIH grants 2R01 DK074720 and R01HL112788, the Stella and Henry Endowment, and the OPUS grant DEC-2016/23/B/NZ3/03157 to MZR. Dr. Abdel-Latif is supported by the University of Kentucky COBRE Early Career Program (P20 GM103527) and the NIH Grant R01 HL124266. MP was supported by NIH T32 HL134644 to MZR. HU’s is supported by grants from the São Paulo Research Foundation FAPESP (Project No. 2012/50880-4) and the National Council for Scientific and Technological Development (CNPq), Brazil.
The online version of this article (https://doi.org/10.1038/s41375-018-0122-0) contains supplementary material, which is available to authorized users
Adamiak, Mateusz; Bujko, Kamila; Cymer, Monika; Plonka, Monika; Glaser, Talita; Kucia, Magda; Ratajczak, Janina; Ulrich, Henning; Abdel-Latif, Ahmed; and Ratajczak, Mariusz Z., "Novel Evidence That Extracellular Nucleotides and Purinergic Signaling Induce Innate Immunity-Mediated Mobilization of Hematopoietic Stem/Progenitor Cells" (2018). Internal Medicine Faculty Publications. 148.
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