Maxime Ruiz

Mesenchymal stem cells for the management of inflammation in osteoarthritis: state of the art and perspectives

Osteoarthritis (OA) is the most common form of degenerative arthritis, mainly characterized by the degradation of articular cartilage and associated with subchondral bone lesions. Novel therapeutic approaches for OA include cell-based therapies that have become thriving areas of research and development. In this context, mesenchymal stem or stromal cells (MSCs) have gained much interest based on their trophic and immunomodulatory properties that can help tissue repair/regeneration. The present review article discusses the interest of using MSCs in cell-therapy approaches with a focus on the mechanisms by which MSCs might exhibit a therapeutic potential in OA. Special attention is given to the anti-inflammatory function of MSCs and on miRNA modulation in OA for possible future innovative strategies. The paper also presents the current data on the undergoing MSCs-based clinical trials in OA.

Therapeutic application of mesenchymal stem cells in osteoarthritis

Introduction: Osteoarthritis (OA) is a degenerative disease characterized by cartilage degradation and subchondral bone alterations. This disease represents a global public health problem whose prevalence is rapidly growing with the increasing aging of the population. With the discovery of mesenchymal stem cells (MSC) as possible therapeutic agents, their potential for repairing cartilage damage in OA is under investigation. Areas covered: Characterization of MSCs and their functional properties are mentioned with an insight into their trophic function and secretory profile. We present a special focus on the types of extracellular vesicles (EVs) that are produced by MSCs and their role in the paracrine activity of MSCs. We then discuss the therapeutic approaches that have been evaluated in pre-clinical models of OA and the results coming out from the clinical trials in patients with OA. Expert opinion: MSC-based therapy seems a promising approach for the treatment of patients with OA. Further research is still needed to demonstrate their efficacy in clinical trials using controlled, prospective studies. However, the emergence of MSC-derived EVs as possible therapeutic agents could be an alternative to cell-based therapy.

Pathogenic or Therapeutic Extracellular Vesicles in Rheumatic Diseases: Role of Mesenchymal Stem Cell-Derived Vesicles

Extracellular vesicles (EVs) are important mediators of cell-to-cell communication pathways via the transport of proteins, mRNA, miRNA and lipids. There are three main types of EVs, exosomes, microparticles and apoptotic bodies, which are classified according to their size and biogenesis. EVs are secreted by all cell types and their function reproduces that of the parental cell. They are involved in many biological processes that regulate tissue homeostasis and physiopathology of diseases. In rheumatic diseases, namely osteoarthritis (OA) and rheumatoid arthritis (RA), EVs have been isolated from synovial fluid and shown to play pathogenic roles contributing to progression of both diseases. By contrast, EVs may have therapeutic effect via the delivery of molecules that may stop disease evolution. In particular, EVs derived from mesenchymal stem cells (MSCs) reproduce the main functions of the parental cells and therefore represent the ideal type of EVs for modulating the course of either disease. The aim of this review is to discuss the role of EVs in OA and RA focusing on their potential pathogenic effect and possible therapeutic options. Special attention is given to MSCs and MSC-derived EVs for modulating OA and RA progression with the perspective of developing innovative therapeutic strategies.

Mesenchymal Stem Cell-Based Therapy of Osteoarthritis: Current Clinical Developments and Future Therapeutic Strategies

Abstract Osteoarthritis (OA) is a very common rheumatic disease that is characterized by cartilage destruction and joint inflammation and leads to significant pain and disability. Various treatment strategies have been proposed for repairing the cartilage damage brought on by OA, but current therapies only alleviate OA symptoms and do not cure the disease. Recently, mesenchymal stem cell (MSC)–based therapies have been proposed and evaluated for treating this disease. In one approach, tissue engineering strategies have been employed to induce the differentiation of MSCs into chondrocytes and generate cartilage tissue upon implantation. While this approach initially aimed to fill focal chondral defects, it was anticipated that it might also delay the development of OA. More recently, a second approach has been considered and relies on the trophic properties of MSCs to stimulate endogenous cartilage regeneration and/or suppress inflammation. In the present review, we aim to provide an update on recent developments in MSC-based therapeutic strategies for OA and a discussion of existing challenges.

04.03 Tgfβ-induced protein (tgfβi) is dysregulated in osteoarthritis

Backgrounds and objectives Osteoarthritis (OA) is the most common rheumatic disease affecting all joint tissues and Transforming Growth Factor β (TGFβ) pathway dysregulation in bone marrow mesenchymal stem cells (MSCs) has been proposed to be involved in OA physiopathology. Based on secretome analysis of MSCs, we identified several TGFβ family members and focused our attention on Transforming Growth Factor β-Induced (TGFβI), a poorly studied extracellular matrix (ECM) component. Materials and methods Human bone marrow MSCs were isolated from OA patients (OA-MSCs) and healthy donors (H-MSCs) while chondrocytes were isolated from OA patients (OA-CH). Chondrogenic differentiation of MSCs was induced in micropellet for 21 days. TGFβI expression was analysed by RT-qPCR and ELISA. Murine articular chondrocytes were isolated from 3 days old C57/BL6 mice and OA-like murine chondrocytes were obtained by addition of 1 ng/mL IL1β for 24 hour. Transfection of siRNA directed against TGFβI (siTGFβI) was performed using oligofectamine. The collagenase-induced murine model of OA was used for immunohistochemical analysis of cartilage and RNA extraction with TRIzol and acid phenol. Results In humans, TGFβI mRNA expression was 2.5 fold lower in OA-MSCs than in H-MSCs and 10 fold lower in OA-MSCs than in OA-CH. We also found out that TGFβI was highly induced (by a 10 fold factor) during the first three days of chondrogenic differentiation but decreased to reach levels similar to those found in MSCs. In the mouse, immunohistochemical analysis revealed high expression of TGFβI in healthy cartilage as compared to OA cartilage. In murine MSCs, expression of TGFβI is 3.8 fold lower than in chondrocytes. In OA-like chondrocytes, characterised by reduced expression of anabolic markers and increased levels of catabolic markers, TGFβI mRNA levels were significantly lower than in healthy chondrocytes. Rapid decline of TGFβI expression was also observed in OA-like dedifferentiated chondrocytes. Finally, transfection of siTGFβI in murine chondrocytes resulted in alteration of their metabolic activity. Conclusion Altogether, our results indicate that expression of TGFβI is higher in articular cartilage than in MSCs, and loss of TGFβI is associated with OA phenotype. TGFβI might be a key regulator of joint homeostasis involved in chondrogenesis and ECM integrity.