title: Mesenchymal stromal cell-secreted chemerin is a novel immunomodulatory molecule driving the migration of ChemR23-expressing cells.
abstract: Mesenchymal stromal cells (MSCs) are multipotent cells characterized by broad immunomodulatory properties exploited for the treatment of inflammatory disorders. However, the efficacy of MSC-based therapy is highly variable and tightly linked to MSC culture conditions and treatment schedule. Thus, the identification of novel key molecules regulating MSC immunomodulatory activities in vivo might constitute a crucial step toward the optimization of currently available clinical protocols. In this regard, herein, we sought to determine whether the newly identified chemotactic protein, chemerin, plays a role in MSC-mediated regulation of inflammation.
  
  
  
  Chemerin production by human MSCs was investigated under different culture conditions using enzyme-linked immunosorbent assay (ELISA). After purification, MSC-secreted chemerin was identified using mass spectrometry analysis and the biological activity of secreted isoforms was evaluated using migration assay.
  
  
  
  Bone marrow-derived MSCs secrete chemerin and express its receptors ChemR23 and CCRL2. Chemerin production is dependent on culture conditions and increases upon stimulation with inflammatory cytokines. In particular, platelet lysate (PL)-MSCs produce higher levels of chemerin compared with fetal bovine serum (FBS)-MSCs. Furthermore, chemerin is secreted by MSCs as an inactive precursor, which can be converted into its active form by exogenous chemerin-activating serine and cysteine proteases.
  
  
  
  Our data indicate that, in response to various inflammatory stimuli, MSCs secrete high amounts of inactive chemerin, which can then be activated by inflammation-induced tissue proteases. In light of these initial findings, we propose that further analysis of chemerin functions in vivo might constitute a crucial step toward optimizing MSC-based therapy for inflammatory diseases.
authors.affiliation: Centro di Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Vinci
authors.affiliation: Istituto di ricovero e cura a carattere scientifico-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Bastone
authors.affiliation: Istituto di ricovero e cura a carattere scientifico-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Schiarea
authors.affiliation: Centro di Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cappuzzello
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Humanitas Clinical and Research Center, Rozzano, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Del Prete
authors.affiliation: Centro di Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Dander
authors.affiliation: Centro di Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy; Clinica Pediatrica, Università di Milano-Bicocca, Fondazione Monza e Brianza per il Bambino e la sua Mamma/Ospedale S. Gerardo, Monza, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Biondi
authors.affiliation: Centro di Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy. Electronic address: giovanna.damico@hsgerardo.org.
authors.forename: Giovanna
authors.initials: G
authors.lastname: D'Amico
mesh_terms: D001792:Blood Platelets / Q000737:chemistry; D018929:Cell Culture Techniques; D002457:Cell Extracts / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects* / Q000235:genetics; D020740:Chimerin Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D003470:Culture Media / Q000378:metabolism / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects* / Q000235:genetics; D007249:Inflammation / Q000378:metabolism / Q000628:therapy; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*
chemical_list: C102741:CMKLR1 protein, human; D002457:Cell Extracts; D020740:Chimerin Proteins; D003470:Culture Media; D019707:Receptors, Chemokine
keywords: ChemR23 receptor; chemerin; immunomodulation; mesenchymal stromal cells