title: Nuclear receptors Nur77 and Nurr1 modulate mesenchymal stromal cell migration.
abstract: 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.
authors.affiliation: Department of Experimental Immunohematology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Marijke W
authors.initials: MW
authors.lastname: Maijenburg
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.forename: Sara M
authors.initials: SM
authors.lastname: Melief
authors.forename: Marion
authors.initials: M
authors.lastname: Kleijer
authors.forename: Kees
authors.initials: K
authors.lastname: Weijer
authors.forename: Anja
authors.initials: A
authors.lastname: Ten Brinke
authors.forename: Helene
authors.initials: H
authors.lastname: Roelofs
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Van Tiel
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Carlie J M
authors.initials: CJ
authors.lastname: de Vries
authors.forename: C Ellen
authors.initials: CE
authors.lastname: van der Schoot
authors.forename: Carlijn
authors.initials: C
authors.lastname: Voermans
mesh_terms: D000077214:Becaplermin; D001853:Bone Marrow / Q000502:physiology*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000494:pharmacology; D005333:Fetus; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D016086:Lentivirus; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics* / Q000378:metabolism; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics* / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D014162:Transfection
chemical_list: D054377:Chemokine CXCL12; C066855:HGF protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; C539821:NR4A1 protein, human; C539882:NR4A2 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D017228:Hepatocyte Growth Factor