MSC; osteoarthritis; senescence; Medicine (miscellaneous); Biochemistry, Genetics and Molecular Biology (all); General Biochemistry, Genetics and Molecular Biology
Abstract :
[en] Senescent cells promote progressive tissue degeneration through the establishment of a combined inflammatory and trophic microenvironment. The cellular senescence state has therefore emerged as a central driving mechanism of numerous age-related diseases, including osteoarthritis (OA), the most common rheumatic disease. Senescence hallmarks are detectable in chondrocytes, synoviocytes and sub-chondral bone cells. This study investigates how the senescence-driven microenvironment could impact the cell fate of resident osteoarticular mesenchymal stromal/stem cells (MSCs) that are hence contributing to OA disease progression. For that purpose, we performed a comparative gene expression analysis of MSCs isolated from healthy donors that were in vitro chronically exposed either to interferon-gamma (IFN-γ) or Transforming Growth Factor beta 1 (TGFβ1), two archetypical factors produced by senescent cells. Both treatments reduced MSC self-renewal capacities by upregulating different senescence-driven cycle-dependent kinase inhibitors. Furthermore, a common set of differentially expressed genes was identified in both treated MSCs that was also found enriched in MSCs isolated from OA patients. These findings highlight an imprinting of OA MSCs by the senescent joint microenvironment that changes their matrisome gene expression. Altogether, this research gives new insights into OA etiology and points to new innovative therapeutic opportunities to treat OA patients.
Disciplines :
Rheumatology
Author, co-author :
Fusi, Giuseppe ; IRMB, University Montpellier, INSERM, 34295 Montpellier, France
Constantinides, Michael; IRMB, University Montpellier, INSERM, 34295 Montpellier, France
Fissoun, Christina; IRMB, University Montpellier, INSERM, 34295 Montpellier, France
Pichard, Lydiane ; SAFE-iPSC Facility INGESTEM, Montpellier University Hospital, 34298 Montpellier, France
Pers, Yves-Marie ; IRMB, University Montpellier, INSERM, 34295 Montpellier, France ; Clinical Immunology and Osteoarticular Diseases Therapeutic Unit, Montpellier University Hospital, 34298 Montpellier, France
Ferreira-Lopez, Rosanna; IRMB, University Montpellier, INSERM, 34295 Montpellier, France ; Clinical Immunology and Osteoarticular Diseases Therapeutic Unit, Montpellier University Hospital, 34298 Montpellier, France
Pantesco, Veronique; IRMB, University Montpellier, INSERM, 34295 Montpellier, France
Poulet, Christophe ; Centre Hospitalier Universitaire de Liège - CHU > > Service de rhumatologie
Malaise, Olivier ; Centre Hospitalier Universitaire de Liège - CHU > > Service de rhumatologie
de Seny, Dominique ; Centre Hospitalier Universitaire de Liège - CHU > > Service de rhumatologie
Lemaitre, Jean-Marc ; IRMB, University Montpellier, INSERM, 34295 Montpellier, France ; SAFE-iPSC Facility INGESTEM, Montpellier University Hospital, 34298 Montpellier, France
Jorgensen, Christian ; IRMB, University Montpellier, INSERM, 34295 Montpellier, France ; Clinical Immunology and Osteoarticular Diseases Therapeutic Unit, Montpellier University Hospital, 34298 Montpellier, France
Brondello, Jean-Marc ; IRMB, University Montpellier, INSERM, 34295 Montpellier, France
INSERM - French Institute of Health and Medical Research [FR] UM - Montpellier University [FR]
Funding text :
This work was supported in part by research funding from the French National Network on Aging (AGEMED) to C.J./J.-M.B., by the EULAR Forum SENOA grant to C.J./J.-M.B. and by the institutional funding from INSERM and Montpellier University to C.J., J.M.L. and J.-M.B.
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