title: Mouse mesenchymal stem cells inhibit high endothelial cell activation and lymphocyte homing to lymph nodes by releasing TIMP-1.
abstract: Mesenchymal stem cells (MSC) represent a promising therapeutic approach in many diseases in view of their potent immunomodulatory properties, which are only partially understood. Here, we show that the endothelium is a specific and key target of MSC during immunity and inflammation. In mice, MSC inhibit activation and proliferation of endothelial cells in remote inflamed lymph nodes (LNs), affect elongation and arborization of high endothelial venules (HEVs) and inhibit T-cell homing. The proteomic analysis of the MSC secretome identified the tissue inhibitor of metalloproteinase-1 (TIMP-1) as a potential effector molecule responsible for the anti-angiogenic properties of MSC. Both in vitro and in vivo, TIMP-1 activity is responsible for the anti-angiogenic effects of MSC, and increasing TIMP-1 concentrations delivered by an Adeno Associated Virus (AAV) vector recapitulates the effects of MSC transplantation on draining LNs. Thus, this study discovers a new and highly efficient general mechanism through which MSC tune down immunity and inflammation, identifies TIMP-1 as a novel biomarker of MSC-based therapy and opens the gate to new therapeutic approaches of inflammatory diseases.
authors.affiliation: Humanitas Clinical and Research Institute, IRCCS, Rozzano, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Zanotti
authors.affiliation: Department of Biomedical Sciences, Venetian Institute of Molecular Medicine (VIMM), Padua, Italy.|University of Padua, Italy, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Angioni
authors.affiliation: Department of Biomedical Sciences, Venetian Institute of Molecular Medicine (VIMM), Padua, Italy.|University of Padua, Italy, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Calì
authors.affiliation: Humanitas Clinical and Research Institute, IRCCS, Rozzano, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Soldani
authors.affiliation: Humanitas Clinical and Research Institute, IRCCS, Rozzano, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Ploia
authors.affiliation: Theodor Kocher Institute, University of Bern, Bern, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Moalli
authors.affiliation: BioInVision Inc., Cleveland, OH, USA.
authors.forename: M
authors.initials: M
authors.lastname: Gargesha
authors.affiliation: Centro Ricerca 'M. Tettamanti,' Clinica Pediatrica Università degli Studi di Milano Bicocca, Monza, Italy.
authors.forename: G
authors.initials: G
authors.lastname: D'Amico
authors.affiliation: Orbsen Therapeutics Ltd, National University of Ireland, Galway, Ireland.
authors.forename: S
authors.initials: S
authors.lastname: Elliman
authors.affiliation: Department of Veterinary Science and Public Health, University of Milano, Milano, Italy.|Filarete Foundation, Milano, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Tedeschi
authors.affiliation: Filarete Foundation, Milano, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Maffioli
authors.affiliation: Department of Veterinary Science and Public Health, University of Milano, Milano, Italy.|Filarete Foundation, Milano, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Negri
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano, Trieste, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Zacchigna
authors.affiliation: INSERM, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Sarukhan
authors.affiliation: Theodor Kocher Institute, University of Bern, Bern, Switzerland.
authors.forename: J V
authors.initials: JV
authors.lastname: Stein
authors.affiliation: Department of Biomedical Sciences, Venetian Institute of Molecular Medicine (VIMM), Padua, Italy.|University of Padua, Italy, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Viola
mesh_terms: D020533:Angiogenesis Inhibitors; D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007249:Inflammation; D008198:Lymph Nodes / Q000166:cytology*; D008214:Lymphocytes / Q000502:physiology*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1