Biology of mesenchymal stem cells and cartilage regeneration
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In the last past years, mesenchymal stem cells (MSCs) have been proved to efficiently treat a variety of diseases (acute injuries, autoimmune diseases, degenerative diseases,…) in pre-clinical models and, are currently evaluated in clinical trials. Meanwhile, the increasing interest of MSCs in regenerative medicine has been ascribed mainly to a paracrine action rather than to direct replacement of the injured tissue. However, there are as yet not adequate explanations for many of the beneficial effects observed although a variety of regulatory and trophic factors are secreted by MSCs. The main objectives of the group are to develop new therapeutic strategies for MSC-based cartilage repair and understand the mechanisms underlying the regenerative properties of MSCs.
Understanding the molecular mechanisms involved in regeneration: application to osteo-articular diseases Paracrine properties of MSC and biotherapies for osteoarthritis. We postulated that MSCs need to be primed by cells from the articular niche to exert a regenerative function in joint diseases. Based on a secretome analysis, we identified proteins that are modulated in ASCs upon coculture with chondrocytes. We are evaluating their therapeutic effect by gain- and loss-of-function assays both in vitro in functional assays and in vivo in the experimental model of collagenase-induced osteoarthritis. Immune properties of MSC and modulation of autoimmune diseases. We previously showed that human ASC are rapidly cleared upon injection in mice while the therapeutic efficacy is maintained at least three weeks in the collagen-induced arthritis (CIA) model. Our recent data suggest that some ASC samples may be less efficient for arthritis suppression. Our objectives are to identify sub-populations of therapeutically active ASCs and define a molecular signature (mRNA or miRNA) that could be markers of efficacy or potency. Systemic sclerosis is a rare autoimmune disease, characterized by skin and lung fibrosis as well as vascular abnormalities. Our preliminary results indicate that MSCs are efficient to reduce skin and lung fibrosis as determined by clinical examination, histology and analysis of fibrotic and inflammatory markers. We aim at optimizing the efficacy of MSCs and investigating the molecular mechanisms that are responsible for the therapeutic benefit, with a particular attention on the oxidative metabolism. Role of exosomes in the trophic effect of MSC. Our hypothesis is that vesicles released by MSCs mediate a critical part of benefits of cell therapy. We are identifying the type of extracellular vesicles that are produced by MSCs, studying the function of the vesicles in vitro, on immune cells and investigating the mediators that are mediating this effect in collaboration with O. Blanc-Brude (Inserm U970). The function of the different types of vesicles is evaluated in the CIA and SSc models. Understanding molecular mechanisms for cartilage formation and development of scaffolds for cartilage engineering In the past decades, there have been numerous attempts to develop tissue-engineered scaffolds to repair chondral defects but there remain significant challenges to be overcome. To address this challenge, we assume that a multidisciplinary approach combining cell biology, biomechanics, biomaterial science and high-throughput analysis is necessary for functional cartilage replacements. The first objective is to identify the molecular mechanisms that control MSC differentiation and regulate the phenotype of mature chondrocytes using transcriptomic analysis. We are validating the role of candidate molecules in dedicated assays in vitro and in vivo. The second objective is to optimize our approaches of cartilage bioengineering using collagen-based microspheres, in collaboration with E. Belamie (CNRS UMR5253). These approaches consist in inhibiting chondrocyte hypertrophy using release of anti-hypertrophic factors or siRNA-expressing nanovectors.
Bibliography
- Ruiz M. TGFβI is involved in the chondrogenic differentiation of mesenchymal stem cells and is dysregulated in osteoarthritis. Osteoarthritis and Cartilage, 2019, 27:493-503.
- Cosenza S. Mesenchymal stem cells derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis. Theranostics 2018, 8:1399-1410. - Maria A. iNOS activity is required for the therapeutic effect of mesenchymal stem cells in experimental systemic sclerosis. Frontiers Immunol, 2018, 9: 3056 - Cosenza S. Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis. Scientific reports, 2017, 7:16214. (IF:4.1) - Maumus M. Thrombospondin-1 partly mediates the cartilage protective effect of adipose-derived mesenchymal stem cells in osteoarthritis. Frontiers Immunol, 2017, 8:1638. - Echalier C. Sol-gel synthesis of collagen-inspired peptide hydrogel. Materials Today 2017, 20: 59-66. (IF:21.7) - Bony C. Adipose mesenchymal stem cells isolated after manual or waterjet-assisted liposuction display similar properties. Frontiers Immunol 2016, 6:655. - Luz-Crawford P. Mesenchymal stem cell-derived IL1RA promotes macrophage polarization and inhibits B cell differentiation. Stem cells, 2016, 34:483-482. - Morille M. PLGA-based microcarriers induce mesenchymal stem cell chondrogenesis and stimulate cartilage repair in osteoarthritis. Biomaterials 2016, 88:60-69. - Vicente R. Deregulation and therapeutic potential of microRNAs in arthritis. Nat Rev Rheum 2016; 12:211-220. - Maria A. Anti-fibrotic, anti-oxidant and immunomodulatory effects of mesenchymal stem cells in HOCl-induced systemic sclerosis. Arthritis Rheum 2016; Oct 16 - Maria A. Human adipose mesenchymal stem cells as potent anti-fibrosis therapy for systemic sclerosis. J. Autoimmunity 2016; 70:31-39. - Maumus M. Utility of a mouse model of osteoarthritis to demonstrate cartilage protection by IFN-γ primed equine mesenchymal stem cells. Frontiers Immunol 2016, 7:392. - Luz-Crawford P. Gilz governs the therapeutic potential of mesenchymal stem cell by inducing a switch from pathogenic to regulatory Th17 cells. Arthr. Rheum, 2015, 67:1514-1524. - Toupet K et al. Long-term detection of human adipose derived mesenchymal stem cells after intra-articular injection. Arthr. Rheum, 2013, 65:1786-1794 More references, click on PubMed:
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Group leader
Danièle NOEL Details
tel: +33 4 67 33 04 73 email: daniele.noel[a]inserm.fr Group
NOEL Danièle (DR2/INSERM) GUILPAIN Philippe (MCU-PH/CHU) PERS Yves-Marie (MCU-PH/CHU) MARIA Alexandre (Chef de clinique/CHU) BONY-GARAYT Claire (IE/INSERM) MAUMUS Marie (IR/privé) TOUPET Karine (IR/CDD UM) LOUSSOUARN Claire (Post doc) BOULESTREAU Jérémy (Doctorant) PETITJEAN Noémie (Doctorante) ROZIER Pauline (Doctorante) SALVADOR Jérémy (Doctorant) THERON Alexandre (Doctorant) BERNARD Laurène (M2) 
Keywords
Mesenchymal stem cell Cartilage Osteo-articular diseases Cell therapy Regeneration Differentiation Immunomodulation Extracellular vesicles Technical skills
Cell biology: mesenchymal stem cell culture and primary chondrocytes ; cell differentiation in vitro ; flux cytrometry ; ELISA, immunofluorescence, Western blot
Purification of extracellular vesicle Immunology: lymphocyte proliferation test ; lymphocyte population identification Molecular biology: RT-qPCR ; TLDA In vivo murine models: collagenase-induiced osteoarthritis, collagen-induiced arthritis, systemic sclerosis, biodistribution studies Cartilage 3D imaging: confocal microscopy, µCT in vivo 
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