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
- Luz-Crawford P et al. Gilz governs the therapeutic potential of mesenchymal stem cell by inducing a switch from pathogenic to regulatory Th17 cells. Arthritis Rheum, 2015, 67:1514-1524. (IF:7.87)
- Djouad F et al. PLZF induction signs mesenchymal stem cell commitment: identification of a key marker for stemness maintenance? Stem Cell Res Ther, 2014, 5:27. (IF:4.63) - Guérit D et al. FoxO3a regulation by miR-29a controls chondrogenic differentiation of mesenchymal stem cells and cartilage formation. Stem Cells Dev, 2014, 23:1195-1205. (IF:4.20) - Mathieu M et al. Induction of mesenchymal stem cell differentiation and cartilage formation by crosslinker-free collagen microspheres. eCM, 2014, 28:82-97. (IF:4.88) - Toupet K et al. Long-term detection of human adipose derived mesenchymal stem cells after intra-articular injection. Arthr. Rheum, 2013, 65:1786-1794. (IF:7.87) - Morille M et al. New PLGA-P188-PLGA matrix enhances TGF-β3 release from pharmacologically active microcarriers and promotes chondrogenesis of mesenchymal stem cells. J. Control Release, 2013, 170:99-110. (IF:7.26) - Manferdini C et al. Adipose stromal cells exert anti-inflammatory effects on chondrocytes and synoviocytes from osteoarthritis patients through PGE2. Arthr. Rheum, 2013, 65:1271-1281. (IF:7.87) - Maumus M et al. Adipose mesenchymal stem cells protect chondrocytes from degeneration associated with osteoarthritis. Stem Cell Res., 2013, 11:834-844. (IF:3,91) - Bouffi C et al. Skin fibroblasts are potent suppressors of inflammation in experimental arthritis. Ann Rheum Dis 2011; 70:1671-1676 (IF:9.27) - Bouffi C et al. The role of pharmacologically active microcarriers releasing TGF-β3 incartilage formation in vivo by mesenchymal stem cells. Biomaterials, 2010; 31:6485-6493c (IF:8,31) 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 
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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