Decreased secretion of MMP by non-lesional late-stage scleroderma fibroblasts after selection via activation of the apoptotic fas-pathway

Authors

  • Stéphane Chabaud,

    1. 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
    2. Département de Chirurgie, Faculté de Médecine, Université Laval, Québec, Québec, Canada
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  • Marie-Pier Corriveau,

    1. 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
    2. Département de Chirurgie, Faculté de Médecine, Université Laval, Québec, Québec, Canada
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  • Tamara Grodzicky,

    1. Laboratoire de Recherche en Auto-immunité, Division of Rheumatology, Centre Hospitalier de l'Université de Montréal (CHUM), Notre Dame Hospital, Montreal, Quebec, Canada
    2. Department of Medicine, Université de Montréal, Montreal, Quebec, Canada
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  • Jean-Luc Senécal,

    1. Laboratoire de Recherche en Auto-immunité, Division of Rheumatology, Centre Hospitalier de l'Université de Montréal (CHUM), Notre Dame Hospital, Montreal, Quebec, Canada
    2. Department of Medicine, Université de Montréal, Montreal, Quebec, Canada
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  • Suzanne Chartier,

    1. Department of Medicine, Université de Montréal, Montreal, Quebec, Canada
    2. Division of Dermatology, CHUM, Montreal, Quebec, Canada
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  • Yves Raymond,

    1. Laboratoire de Recherche en Auto-immunité, Division of Rheumatology, Centre Hospitalier de l'Université de Montréal (CHUM), Notre Dame Hospital, Montreal, Quebec, Canada
    2. Department of Medicine, Université de Montréal, Montreal, Quebec, Canada
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  • Véronique J. Moulin

    Corresponding author
    1. 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
    2. Département de Chirurgie, Faculté de Médecine, Université Laval, Québec, Québec, Canada
    • LOEX, aile R, Centre Hospitalier affilié Universitaire de Québec, 1401, 18e rue, Québec, Québec, Canada G1J 1Z4.
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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. J. Cell. Physiol. 226: 1907–1914, 2011. © 2010 Wiley-Liss, Inc.

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