Mesenchymal stem cell-based therapies in regenerative medicine: applications in rheumatology

Growing knowledge on the biology of mesenchymal stem cells (MSCs) has provided new insights into their potential clinical applications, particularly for rheumatologic disorders. Historically, their potential to differentiate into cells of the bone and cartilage lineages has led to a variety of experimental strategies to investigate whether MSCs can be used for tissue engineering approaches. Beyond this potential, MSCs also display immunosuppressive properties, which have prompted research on their capacity to suppress local inflammation and tissue damage in a variety of inflammatory autoimmune diseases and, in particular, in rheumatoid arthritis. Currently, an emerging field of research comes from the possibility that these cells, through their trophic/regenerative potential, may also influence the course of chronic degenerative disorders and prevent cartilage degradation in osteoarthritis. This review focuses on these advances, specifically on the biological properties of MSCs, including their immunoregulatory characteristics, differentiation capacity and trophic potential, as well as the relevance of MSC-based therapies for rheumatic diseases

Effective Gene Therapy in a Mouse Model of Prion Diseases

Classical drug therapies against prion diseases have encountered serious difficulties. It has become urgent to develop radically different therapeutic strategies. Previously, we showed that VSV-G pseudotyped FIV derived vectors carrying dominant negative mutants of the PrP gene are efficient to inhibit prion replication in chronically prion-infected cells. Besides, they can transduce neurons and cells of the lymphoreticular system, highlighting their potential use in gene therapy approaches. Here, we used lentiviral gene transfer to deliver PrPQ167R virions possessing anti-prion properties to analyse their efficiency in vivo. Since treatment for prion diseases is initiated belatedly in human patients, we focused on the development of a curative therapeutic protocol targeting the late stage of the disease, either at 35 or 105 days post-infection (d.p.i.) with prions. We observed a prolongation in the lifespan of the treated mice that prompted us to develop a system of cannula implantation into the brain of prion-infected mice. Chronic injections of PrPQ167R virions were done at 80 and 95 d.p.i. After only two injections, survival of the treated mice was extended by 30 days (20%), accompanied by substantial improvement in behaviour. This delay was correlated with: (i) a strong reduction of spongiosis in the ipsilateral side of the brain by comparison with the contralateral side; and (ii) a remarkable decrease in astrocytic gliosis in the whole brain. These results suggest that chronic injections of dominant negative lentiviral vectors into the brain, may be a promising approach for a curative treatment of prion diseases

L’information cachée dans le repliement des protéines

Les recherches sur les prions et sur les phénomènes d’agrégation des peptides et des protéines ont permis des avancées conceptuelles significatives en biologie conduisant à de nouvelles perspectives thérapeutiques. Du point de vue moléculaire, l’analyse de phénomènes « prions » présents également dans les levures et les champignons filamenteux, a permis de confirmer l’existence d’une transmission d’une information biologique basée sur la conformation des protéines. Cette découverte représente une nouvelle facette des mécanismes épigénétiques qui laisse envisager pour ce mécanisme « prion » des fonctions physiologiques importantes. L’étude des mécanismes d’agrégation des protéines trouve un écho dans une large gamme de pathologies allant de la maladie de Parkinson au diabète. Dans ces protéinopathies, des mécanismes moléculaires similaires ont pu être mis à jour avec pour conséquence des modèles de changements de conformation et d’approches diagnostiques et thérapeutiques communs à ces pathologies

An injectable copolymer of fatty acids (ARA 3000 BETA) as a promising treatment for osteoarthritis

Abstract Osteoarthritis (OA) is the most prevalent rheumatic disease and a fast growing cause of disability. Current pharmacological treatments include antalgics and non-steroid anti-inflammatory drugs to control pain and inflammation as well as slow acting drugs such as intra-articular (IA) administration of hyaluronic acid. Oral supplementation or diet rich in polyunsaturated free fatty acids are proposed but evidence for benefit is still under debate. We here investigated the therapeutic potential of ARA 3000 BETA, an injectable copolymer of fatty acids, at the structural level in OA. Collagenase-induced osteoarthritis model was induced in C57BL/6 mice by collagenase injection into knee joint. Mice were treated with one or two IA or four intra-muscular injections (IM) of ARA 3000 BETA. At sacrifice, knee joints were recovered for cartilage analysis by confocal laser scanning microscopy (CLSM) and bone analysis by micro-computed tomography system. OA histological scoring was performed after safranin O/fast green staining. Histological analysis revealed a protective effect against cartilage degradation in treated knee joints after IM and IA administration. This was confirmed by CLSM with a significant improvement of all articular cartilage parameters, including thickness, volume and surface degradation whatever the administration route. A slight protective effect was also noticed on subchondral bone parameters and knee joint calcification after IM administration and to a lesser extent, two IA injections. We demonstrated the therapeutic efficacy of injectable ARA 3000 BETA in OA with a protection against cartilage and bone alterations providing the proof-of-concept that clinical translation might be envisioned to delay disease progression

Stratégies thérapeutiques des maladies à prions

Les maladies à prions sont des maladies neurodégénératives qui touchent l'homme et l'animal, et dont l'issue est fatale. Ces maladies sont provoquées par l'accumulation dans le cerveau de la PrPSc, l'isoforme mal repliée de la protéine prion cellulaire. L'apparition de nouveaux risques de transmission de ces maladies et l'absence de traitement efficace, nous ont incité à explorer de nouvelles stratégies et cibles thérapeutiques. Nous avons développé deux approches thérapeutiques innovantes. La première à consister à rechercher des molécules capables de piéger les formes préamyloïdes de la PrPSc (dimères et trimères), décrites comme éléments essentiels du cycle de réplication des prions. Une technique de criblage de drogues in silico et in cellulo nous a permis de mettre en évidence des composés thiényl pyrimidiques et thiényl azines capables d'oligomériser spécifiquement la PrPSc. Ces oligomères de PrPSc réduisent l'infectiosité des prions in vivo, soulignant le potentiel thérapeutique de ces composés. Notre deuxième stratégie est une stratégie de thérapie génique utilisant les propriétés dominantes négatives de certains polymorphismes de la protéine prion, comme les mutants Q218K et Q167R. Notre objectif a été d'évaluer le potentiel thérapeutique de vecteurs lentiviraux portant les mutants PrPQ218K et PrPQ167R, chez des souris au stade tardif de la maladie. Nous avons réussi à prolonger significativement la durée de vie des souris de 20% grâce à 2 injections chroniques de vecteurs lentiviraux portant le mutant PrPQ167R. Nos résultats ouvre la voie sur de nouvelles perspespectives thérapeutiques pour les maladies à prions et autres maladies neurodégénérativesPrion diseases are fatal neurodegenerative disorders that affect both humans and animals. These diseases are induced by the accumulation in the brain of the misfolded isoform of the normal cellular prion protein: PrPSc. The emergence of new risks of transmission for these diseases and the lack of efficient treatments, prompt us to search for new therapeutic strategies and targets. We developed two innovative therapeutic approaches. The first one consisted in searching for molecules able to trap preamyloid forms of PrPSc (dimers and trimers), known as key elements in the replication cycle of prions. A drugs screening approach, in silico and in cellulo, allowed us to discover thienyl pyrimidine and thienyl azine compounds able to specifically oligomerize PrPSc molecules. These PrPSc oligomers decrease prions infectivity in vivo, highlighting the therapeutic potential of these compounds. Our second strategie is a gene therapy approach using the dominant negative properties of certain polymorphisms of the prion protein, such as the Q218K and Q167R mutants. Our objective was to evaluate the therapeutic potential of lentiviral vectors carrying the PrPQ218K and PrPQ167R mutants, in mice, at the terminal stage of the disease. We succeeded in significantly prolonging the survival time of mice of 20%, with two intracerebrally chronic injections of lentiviral vectors carrying the PrPQ167R mutant. All our results not only open the way for new therapeutic strategies against prion diseases but also will benefit for therapies of other neurodegenerative disordersMONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis

Abstract Mesenchymal stem or stromal cells (MSCs) exert chondroprotective effects in preclinical models of osteoarthritis (OA). Most of their therapeutic effects are mediated via soluble mediators, which can be conveyed within extracellular vesicles (EVs). The objective of the study was to compare the respective role of exosomes (Exos) or microvesicles/microparticles (MPs) in OA. MPs and Exos were isolated from bone marrow murine BM-MSCs through differential centrifugation. Effect of MPs or Exos was evaluated on OA-like murine chondrocytes and chondroprotection was quantified by RT-qPCR. In OA-like chondrocytes, BM-MSC-derived MPs and Exos could reinduce the expression of chondrocyte markers (type II collagen, aggrecan) while inhibiting catabolic (MMP-13, ADAMTS5) and inflammatory (iNOS) markers. Exos and MPs were also shown to protect chondrocytes from apoptosis and to inhibit macrophage activation. In vivo, Exos or MPs were injected in the collagenase-induced OA (CIOA) model and histomorphometric analyses of joints were performed by µCT and confocal laser microscopy. BM-MSCs, MPs and Exos equally protected mice from joint damage. In conclusion, MPs and Exos exerted similar chondroprotective and anti-inflammatory function in vitro and protected mice from developing OA in vivo, suggesting that either Exos or MPs reproduced the main therapeutic effect of BM-MSCs

PLGA-based microcarriers induce mesenchymal stem cell chondrogenesis and stimulate cartilage repair in osteoarthritis

International audienc

Electron-Rich Piano-Stool Iron σ-Acetylides. † Theoretical and Phenomenological Investigation of Electronic Substituent Effects in Iron(II) Acetylides

International audienc