Nuclear receptors Nur77 and Nurr1 modulate mesenchymal stromal cell migration

• Published in: Stem cells and development Vol. 21; no. 2; p. 228
• Main Authors: Maijenburg, Marijke W, Gilissen, Christian, Melief, Sara M, Kleijer, Marion, Weijer, Kees, Ten Brinke, Anja, Roelofs, Helene, Van Tiel, Claudia M, Veltman, Joris A, de Vries, Carlie J M, van der Schoot, C Ellen, Voermans, Carlijn
• Format: Journal Article
• Language: English
• Published: United States 20.01.2012
• Subjects: Bone Marrow - physiology; Cell Cycle - drug effects; Cell Cycle - genetics; Cell Movement - drug effects; Cell Movement - genetics; Cell Proliferation - drug effects; Cells, Cultured; Chemokine CXCL12 - pharmacology; Fetus; Gene Expression Profiling; Gene Expression Regulation - drug effects; Hepatocyte Growth Factor - genetics; Hepatocyte Growth Factor - metabolism; Humans; Interleukin-6 - biosynthesis; Interleukin-8 - biosynthesis; Lentivirus; Mesenchymal Stromal Cells - cytology; Mesenchymal Stromal Cells - drug effects; Mesenchymal Stromal Cells - metabolism; Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics; Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism; Nuclear Receptor Subfamily 4, Group A, Member 2 - genetics; Nuclear Receptor Subfamily 4, Group A, Member 2 - metabolism; Proto-Oncogene Proteins c-sis - pharmacology; Signal Transduction - drug effects; T-Lymphocytes - cytology; T-Lymphocytes - metabolism; Transfection
• DOI: 10.1089/scd.2011.0076

Detailed understanding of mesenchymal stromal cells (MSC) migration is imperative for future cellular therapies. To identify genes involved in the process of MSC migration, we generated gene expression profiles of migrating and nonmigrating fetal bone marrow MSC (FBMSC). Only 12 genes showed differential expression in migrating versus nonmigrating FBMSC. The nuclear receptors Nur77 and Nurr1 showed the highest expression in migratory MSC. Nur77 and Nurr1 are members of NR4A nuclear orphan receptor family, and we found that their expression is rapidly increased upon exposure of FBMSC to the migratory stimuli stromal-derived factor-1α (SDF-1α) and platelet-derived growth factor-BB. Lentiviral expression of Nur77 or Nurr1 resulted in enhanced migration of FBMSC toward SDF-1α compared with mock-transduced FBMSC. Analysis of the cell cycle, known to be involved in MSC migration, revealed that expression of Nur77 and Nurr1 decreases the proportion of cells in S-phase compared with control cells. Further, gain-of-function experiments showed increased hepatocyte growth factor expression and interleukin (IL)-6 and IL-8 production in MSC. Despite the altered cytokine profile, FBMSC expressing Nur77 or Nurr1 maintained the capacity to inhibit T-cell proliferation in a mixed lymphocyte reaction. Our results demonstrate that Nur77 and Nurr1 promote FBMSC migration. Modulation of Nur77 and Nurr1 activity may therefore offer perspectives to enhance the migratory potential of FBMSC which may specifically regulate the local immune response.