title: Urokinase receptor mediates mobilization, migration, and differentiation of mesenchymal stem cells.
abstract: OBJECTIVE
  Multipotent mesenchymal stem cells (MSCs) have regenerative properties and are recognized as putative players in the pathogenesis of cardiovascular diseases. The underlying molecular mechanisms remain, however, sparsely explored. Our study was designed to elucidate a probable role for the multifunctional urokinase (uPA)/urokinase receptor (uPAR) system in MSC regulation. Though uPAR has been implicated in a broad spectrum of pathophysiological processes, nothing is known about uPAR in MSCs.
  
  
  RESULTS
  uPAR was required to mobilize MSCs from the bone marrow (BM) of mice stimulated with granulocyte colony-stimulating factor (G-CSF) in vivo. An insignificant amount of MSCs was mobilized in uPAR(-/-) C57BL/6J mice, whereas in wild-type animals G-CSF induced an eight-fold increase of mobilized MSCs. uPAR(-/-) mice revealed up-regulated expression of G-CSF and stromal cell-derived factor 1 (CXCR4) receptors in BM. uPAR down-regulation leads to inhibition of human MSC migration, as shown in different migration assays. uPAR down- or up-regulation resulted in inhibition or stimulation of MSC differentiation into vascular smooth muscle cells (VSMCs) correspondingly, as monitored by changes in cell morphology and expression of specific marker proteins. Injection of fluorescently labelled MSCs in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice after femoral artery wire injury demonstrated impaired engraftment of uPAR-deficient MSCs at the place of injury.
  
  
  CONCLUSIONS
  These data suggest a multifaceted function of uPAR in MSC biology contributing to vascular repair. uPAR might guide and control the trafficking of MSCs to the vascular wall in response to injury or ischaemia and their differentiation towards functional VSMCs at the site of arterial injury.
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover D-30625, Germany.
authors.forename: Krishna C
authors.initials: KC
authors.lastname: Vallabhaneni
authors.forename: Sergey
authors.initials: S
authors.lastname: Tkachuk
authors.forename: Yulia
authors.initials: Y
authors.lastname: Kiyan
authors.forename: Nelli
authors.initials: N
authors.lastname: Shushakova
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.forename: Inna
authors.initials: I
authors.lastname: Dumler
authors.forename: Gabriele
authors.initials: G
authors.lastname: Eden
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D048430:Cell Shape; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000378:metabolism / Q000473:pathology; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D057809:HEK293 Cells; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009131:Muscle, Smooth, Vascular / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D034622:RNA Interference; D019718:Receptors, CXCR4 / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D057772:Vascular System Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery
chemical_list: D015415:Biomarkers; C514936:CXCR4 protein, mouse; C524898:PLAUR protein, human; C524899:Plaur protein, mouse; D019718:Receptors, CXCR4; D055293:Receptors, Urokinase Plasminogen Activator; D016179:Granulocyte Colony-Stimulating Factor