title: Decreased secretion of MMP by non-lesional late-stage scleroderma fibroblasts after selection via activation of the apoptotic Fas-pathway.
abstract: Our hypothesis is that the development of lesional areas of skin in patients with systemic sclerosis (SSc) originates from the selection of profibrotic cell subpopulations within their non-lesional skin areas, due to their greater resistance to apoptosis. Sensitivity to apoptosis of early-stage or late-stage SSc fibroblasts as well as of healthy cells was compared using extrinsic or intrinsic apoptotic pathway-inducers. Subpopulations of non-lesional SSc cells and healthy cells obtained after repeated Fas-induced apoptosis were compared with respect to their fibrotic parameters such as collagen and MMP secretion. Only late-stage lesional SSc cells were more resistant to Fas-induced apoptosis than their non-lesional counterparts isolated from the same patient. This result correlated with an increase in the levels of the anti-apoptotic proteins cFLIPs and cIAP in lesional cells compared to non-lesional cells. Healthy and non-lesional cell populations could be selected to generate a subpopulation that was more resistant to apoptosis. However, only the late-stage non-lesional SSc fibroblast populations showed a significant decrease in MMP secretion, one of parameters of the fibrosis. Our results show that resistance to apoptosis is an important characteristic of the late-stage lesional SSc fibroblast phenotype. We thus hypothesized that a selection of specific fibroblast subpopulations from late-stage non-lesional SSc skin areas could be at the origin of lesional populations. These cells should become independent of any exogenous stimuli and can induce or maintain SSc skin lesions.
authors.affiliation: Centre LOEX de l'Université Laval, Génie Tissulaire et régénération: LOEX-Centre de Recherche FRSQ du Centre hospitalier affilié universitaire de Québec, Québec, Québec, Canada.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Chabaud
authors.forename: Marie-Pier
authors.initials: MP
authors.lastname: Corriveau
authors.forename: Tamara
authors.initials: T
authors.lastname: Grodzicky
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Senécal
authors.forename: Suzanne
authors.initials: S
authors.lastname: Chartier
authors.forename: Yves
authors.initials: Y
authors.lastname: Raymond
authors.forename: Véronique J
authors.initials: VJ
authors.lastname: Moulin
mesh_terms: D000328:Adult; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D015536:Down-Regulation; D053222:Fas Ligand Protein / Q000378:metabolism*; D005347:Fibroblasts / Q000201:enzymology* / Q000473:pathology; D005355:Fibrosis; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D053505:Matrix Metalloproteinases, Secreted / Q000378:metabolism*; D008875:Middle Aged; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D045743:Scleroderma, Diffuse / Q000175:diagnosis / Q000201:enzymology* / Q000473:pathology; D015398:Signal Transduction; D012867:Skin / Q000201:enzymology* / Q000473:pathology; D019014:fas Receptor / Q000378:metabolism
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C491901:FAS protein, human; D053222:Fas Ligand Protein; D051034:Inhibitor of Apoptosis Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D053505:Matrix Metalloproteinases, Secreted