Inducible Nitric Oxide Synthase (iNOS) Is a Novel Negative Regulator of Hematopoietic Stem/Progenitor Cell Trafficking

• DOI: 10.1007/s12015-016-9693-1
• Publication Date: 2016-10-17T12:37:23Z
• Authors: Mateusz Adamiak; Ahmed Abdelbaset-...; Joseph B. Moore; J Zhao; Ahmed Abdel-Latif; Marcin Wysoczynski; Mariusz Z. Ratajczak
• Keywords: 0301 basic medicine; Cancer Research; Blotting, Western; Nitric Oxide Synthase Type II; Bone Marrow Cells; Nitric Oxide; Article; Gene Expression Regulation, Enzymologic; 03 medical and health sciences; Cell Movement; Cell Line, Tumor; Cell Adhesion; Animals; Humans; Cells, Cultured; Mice, Knockout; Chemotaxis; Cell Biology; Hematopoietic Stem Cells; Hematopoietic Stem Cell Mobilization; 3. Good health; Mice, Inbred C57BL; Female; RNA Interference; K562 Cells; Heme Oxygenase-1; Developmental Biology

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.