Nitric oxide (NO) is a gaseous free radical molecule involved in several biological processes related to inflammation, tissue damage, and infections. Based on reports that NO inhibits migration of granulocytes and monocytes, we became interested in the role of inducible NO synthetase (iNOS) in pharmacological mobilization of hematopoietic stem/progenitor cells (HSPCs) from bone marrow (BM) into peripheral blood (PB). To address the role of NO in HSPC trafficking, we upregulated or downregulated iNOS expression in hematopoietic cell lines. Next, we performed mobilization studies in iNOS−/− mice and evaluated engraftment of iNOS−/− HSPCs in wild type (control) animals. Our results indicate that iNOS is a novel negative regulator of hematopoietic cell migration and prevents egress of HSPCs into PB during mobilization. At the molecular level, downregulation of iNOS resulted in downregulation of heme oxygenase 1 (HO-1), and, conversely, upregulation of iNOS enhanced HO-1 activity. Since HO-1 is a negative regulator of cell migration, the inhibitory effects of iNOS identified by us can be at least partially explained by its enhancing the HO-1 level in BM cells.
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This work was supported by NIH grants 2R01 DK074720 and R01HL112788, the Stella and Henry Endowment, and the Harmonia NCN grant UMO-2014/14/M/NZ3/00475 to MZR.
The online version of this article (doi: 10.1007/s12015-016-9693-1) contains supplementary material, which is available to authorized users.
Adamiak, Mateusz; Abdelbaset-Ismail, Ahmed; Moore, Joseph B. IV; Zhao, J.; Abdel-Latif, Ahmed; Wysoczynski, Marcin; and Ratajczak, Mariusz Z., "Inducible Nitric Oxide Synthase (iNOS) Is a Novel Negative Regulator of Hematopoietic Stem/Progenitor Cell Trafficking" (2017). Internal Medicine Faculty Publications. 184.