title: Characterization of Gaucher disease bone marrow mesenchymal stromal cells reveals an altered inflammatory secretome.
abstract: Gaucher disease causes pathologic skeletal changes that are not fully explained. Considering the important role of mesenchymal stromal cells (MSCs) in bone structural development and maintenance, we analyzed the cellular biochemistry of MSCs from an adult patient with Gaucher disease type 1 (N370S/L444P mutations). Gaucher MSCs possessed a low glucocerebrosidase activity and consequently had a 3-fold increase in cellular glucosylceramide. Gaucher MSCs have a typical MSC marker phenotype, normal osteocytic and adipocytic differentiation, growth, exogenous lactosylceramide trafficking, cholesterol content, lysosomal morphology, and total lysosomal content, and a marked increase in COX-2, prostaglandin E2, interleukin-8, and CCL2 production compared with normal controls. Transcriptome analysis on normal MSCs treated with the glucocerebrosidase inhibitor conduritol B epoxide showed an up-regulation of an array of inflammatory mediators, including CCL2, and other differentially regulated pathways. These cells also showed a decrease in sphingosine-1-phosphate. In conclusion, Gaucher disease MSCs display an altered secretome that could contribute to skeletal disease and immune disease manifestations in a manner distinct and additive to Gaucher macrophages themselves.
authors: Montreal Centre for Experimental Therapeutics in Cancer, Lady Davis Institute for Medical Research, Montreal, QC, Canada.
authors: Philippe M
authors: PM
authors: Campeau
authors: Moutih
authors: M
authors: Rafei
authors: Marie-Noëlle
authors: MN
authors: Boivin
authors: Ying
authors: Y
authors: Sun
authors: Gregory A
authors: GA
authors: Grabowski
authors: Jacques
authors: J
authors: Galipeau
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D019943:Amino Acid Substitution; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005776:Gaucher Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005963:Glucosylceramides / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D007294:Inositol / Q000031:analogs & derivatives / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010011:Osteocytes / Q000378:metabolism / Q000473:pathology; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: C111835:CCL2 protein, human; C508606:CXCL8 protein, human; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D005963:Glucosylceramides; D018836:Inflammation Mediators; D016209:Interleukin-8; D007294:Inositol; D002784:Cholesterol; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D005962:Glucosylceramidase; D015232:Dinoprostone; C011423:conduritol epoxide