title: The Adipose Mesenchymal Stem Cell Secretome Inhibits Inflammatory Responses of Microglia: Evidence for an Involvement of Sphingosine-1-Phosphate Signalling.
abstract: Central nervous system (CNS) inflammation is primarily driven by microglial cells which secrete proinflammatory cytokines and undergo proliferation upon activation, as it occurs in neurodegenerative diseases. Uncontrolled or prolonged CNS inflammation is potentially harmful and can result in cellular damage. Recently, many studies have focused on human adipose tissue as an attractive source of cytokines with immunosuppressive properties that potentially modulate inflammation. Our study aimed to evaluate if different methods of human tissue collection could affect adipose mesenchymal stem cell (ADSC)-derived cytokine secretion and investigate the effects of ADSC secretome in modulating microglia activation and the possible implication of sphingosine-1-phosphate (S1P) in these effects. Our results demonstrate that the conditioned medium (CM) of ADSCs isolated by two different processing methods (lipoaspirate and Lipogems) significantly inhibited the lipopolysaccharide (LPS)-induced effects on microglia activation, including microglial expression of CD68, cytokine secretion, proliferation, and migration. Pulse studies with radiolabeled sphingosine demonstrated that LPS treatment of resting microglia induced a significant increase of both cellular and extracellular S1P. Moreover, and of relevance, FTY720, a functional antagonist of S1P receptor, inhibited the multiple LPS-induced proinflammatory effects on microglia, and S1P suppressed the anti-inflammatory effect of ADSC-CM. This suggests that LPS-mediated microglial activation is countered by ADSC-CM through the modulation of sphingosine kinase/S1P signalling.
authors.affiliation: 1 Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, University of Milan , Milan, Italy .
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marfia
authors.affiliation: 1 Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, University of Milan , Milan, Italy .
authors.forename: Stefania Elena
authors.initials: SE
authors.lastname: Navone
authors.affiliation: 2 Department of Medical Biotechnology and Translational Medicine, LITA-Segrate, University of Milan , Milan, Italy .
authors.forename: Loubna Abdel
authors.initials: LA
authors.lastname: Hadi
authors.affiliation: 3 Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," Milan, Italy .
authors.forename: Moira
authors.initials: M
authors.lastname: Paroni
authors.affiliation: 3 Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," Milan, Italy .
authors.forename: Valeria
authors.initials: V
authors.lastname: Berno
authors.affiliation: 1 Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, University of Milan , Milan, Italy .
authors.forename: Matteo
authors.initials: M
authors.lastname: Beretta
authors.affiliation: 4 Division of Rheumatology, Istituto Gaetano Pini , Milano, Italy .
authors.forename: Roberta
authors.initials: R
authors.lastname: Gualtierotti
authors.affiliation: 4 Division of Rheumatology, Istituto Gaetano Pini , Milano, Italy .
authors.forename: Francesca
authors.initials: F
authors.lastname: Ingegnoli
authors.affiliation: 1 Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, University of Milan , Milan, Italy .
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Levi
authors.affiliation: 5 Division of Pathology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, University of Milan , Milan, Italy .
authors.forename: Monica
authors.initials: M
authors.lastname: Miozzo
authors.affiliation: 3 Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," Milan, Italy .
authors.forename: Jens
authors.initials: J
authors.lastname: Geginat
authors.affiliation: 6 Department of Health Sciences and Industrial and Information Engineering, University of Pavia , Pavia, Italy .
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Fassina
authors.affiliation: 1 Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, University of Milan , Milan, Italy .
authors.forename: Paolo
authors.initials: P
authors.lastname: Rampini
authors.affiliation: 7 Istituto Image , Milan, Italy .
authors.forename: Carlo
authors.initials: C
authors.lastname: Tremolada
authors.affiliation: 2 Department of Medical Biotechnology and Translational Medicine, LITA-Segrate, University of Milan , Milan, Italy .
authors.forename: Laura
authors.initials: L
authors.lastname: Riboni
authors.affiliation: 1 Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, University of Milan , Milan, Italy .
authors.forename: Rolando
authors.initials: R
authors.lastname: Campanella
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000328:Adult; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D002633:Chemotaxis / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D008070:Lipopolysaccharides; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017628:Microglia / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D010641:Phenotype; D020543:Proteome / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D008070:Lipopolysaccharides; D008246:Lysophospholipids; D020543:Proteome; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine