title: Low FasL levels promote proliferation of human bone marrow-derived mesenchymal stem cells, higher levels inhibit their differentiation into adipocytes.
abstract: Mesenchymal stem cells (MSCs) are multipotent progenitor cells that can differentiate into several cell types. Bone marrow (BM)-MSCs mainly differentiate into osteoblasts or adipocytes. MSC interactions with their microenvironment directly affect their self-renewal/differentiation program. Here, we show for the first time that Fas ligand (FasL), a well-explored proapoptotic cytokine, can promote proliferation of BM-derived MSCs in vitro and inhibits their differentiation into adipocytes. BM-MSCs treated with a low FasL dose (0.5 ng/ml) proliferated more rapidly than untreated cells without undergoing spontaneous differentiation or apoptosis, whereas higher doses (25 ng/ml) induced significant though not massive BM-MSC death, with surviving cells maintaining a stem cell phenotype. At the molecular level, 0.5 ng/ml FasL induced ERK1/2 phosphorylation and survivin upregulation, whereas 25 ng/ml FasL induced caspase activation. Importantly, 25 ng/ml FasL reversibly prevented BM-MSC differentiation into adipocytes by modulating peroxisome proliferator-activated receptor gamma (PPARγ) and FABP4/aP2 expression induced by adipogenic medium. All such effects were inhibited by anti-Fas neutralizing antibody. The in vitro data regarding adipogenesis were confirmed using Fas(lpr) mutant mice, where higher PPARγ and FABP4/aP2 mRNA and protein levels were documented in whole tibia. These data show for the first time that the FasL/Fas system can have a role in BM-MSC biology via regulation of both proliferation and adipogenesis, and may have clinical relevance because circulating Fas/FasL levels decline with age and several age-related conditions, including osteoporosis, are characterized by adipocyte accumulation in BM.
authors.affiliation: Laboratory of Experimental Pathology, Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Ancona, Italy. m.r.rippo@univpm.it
authors.forename: M R
authors.initials: MR
authors.lastname: Rippo
authors.forename: L
authors.initials: L
authors.lastname: Babini
authors.forename: F
authors.initials: F
authors.lastname: Prattichizzo
authors.forename: L
authors.initials: L
authors.lastname: Graciotti
authors.forename: G
authors.initials: G
authors.lastname: Fulgenzi
authors.forename: F
authors.initials: F
authors.lastname: Tomassoni Ardori
authors.forename: F
authors.initials: F
authors.lastname: Olivieri
authors.forename: G
authors.initials: G
authors.lastname: Borghetti
authors.forename: S
authors.initials: S
authors.lastname: Cinti
authors.forename: A
authors.initials: A
authors.lastname: Poloni
authors.forename: F
authors.initials: F
authors.lastname: Fazioli
authors.forename: A D
authors.initials: AD
authors.lastname: Procopio
mesh_terms: D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology*; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D000077022:Survivin; D013977:Tibia / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; C107489:BIRC5 protein, human; C493410:FABP4 protein, human; D053222:Fas Ligand Protein; D050556:Fatty Acid-Binding Proteins; D051034:Inhibitor of Apoptosis Proteins; D047495:PPAR gamma; D011994:Recombinant Proteins; D000077022:Survivin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020169:Caspases