Culture and Use of Mesenchymal Stromal Cells in Phase I and II Clinical Trials

Present in numerous tissues, mesenchymal stem cells/multipotent stromal cells (MSCs) can differentiate into different cell types from a mesoderm origin. Their potential has been extended to pluripotency, by their possibility of differentiating into tissues and cells of nonmesodermic origin. Through the release of cytokines, growth factors and biologically active molecules, MSCs exert important paracrine effects during tissue repair and inflammation. Moreover, MSCs have immunosuppressive properties related to non-HLA restricted immunosuppressive capacities. All these features lead to an increasing range of possible applications of MSCs, from treating immunological diseases to tissue and organ repair, that should be tested in phase I and II clinical trials. The most widely used MSCs are cultured from bone marrow or adipose tissue. For clinical trial implementation, BM MSCs and ADSCs should be produced according to Good Manufacturing Practices. Safety remains the major concern and must be ensured during culture and validated with relevant controls. We describe some applications of MSCs in clinical trials

Broad-Spectrum Antibacterial Effects of Human Adipose-Derived Stromal Cells

Introduction. Many pathological conditions may benefit from cell therapy using mesenchymal stromal cells, particularly from adipose tissue (ASCs). Cells may be grafted in an environment with a remnant polymicrobial component. The aim is to investigate the behavior of ASCs when brought in contact with a large panel of bacteria. Materials and Methods. Carboxyfluorescein-labelled bacterial interaction with ASCs was followed by confocal time-lapse microscopy. Costaining with LAMP-1 was also analyzed. Viability of 4 gram-negative and 4 gram-positive bacterial strains after 6 h of coculture with ASCs was assessed by agar colony counting and by flow cytometry using SYTO-62®/propidium iodide (PI) for membrane permeabilization and DiOC6 for depolarization. A murine model of periodontitis was used to assess in vivo antibacterial capacities of ASCs. Results. A significant increase of PI-positive events for all bacterial strains and an increase of the DiOC6 signal were obtained after contact with ASCs. The number of CFU was also significantly decreased for several bacterial strains. 0.4 μm transwell systems illustrated the necessary direct contact to induce maximal bacterial membrane damages. Some bacteria were observed into phagolysosomes, confirming macrophage-like properties of ASCs. In vivo, the bacterial load was significantly lower in the ASC-grafted side compared to the control. Conclusion. Our results highlight for the first time a broad range of antibacterial actions of ASCs, by phagocytosis, secretion of oxygenated free radicals and antibacterial molecules. These data are in line with the development of new therapeutic strategies based on ASC transplantation, appropriated in immune-dysbiotic tissue context such as periodontitis or chronic wounds

Le tissu adipeux : une écologie cellulaire subtile et complexe

Le tissu adipeux est l'un des tissus les plus abondants du corps humain. Le tissu adipeux blanc est composé de deux populations cellulaires qui peuvent être séparées facilement, les adipocytes matures d'une part et, d'autre part, la fraction stroma-vasculaire (SVF). Celle-ci contient deux compartiments, l'un stromal et l'autre hématopoïétique, qui ont été récemment caractérisés. La population stromale (ou ADAS) présente des analogies fonctionnelles ainsi qu'une relation de lignage avec les macrophages. Ces cellules qui peuvent également se différencier en adipocytes ou en cellules endothéliales peuvent être considérées comme des progéniteurs vasculaires. Il a également été montré que certaines cellules présentes dans le tissu adipeux pouvaient se différencier in vitro ou in vivo en ostéoblastes, chondrocytes, cardiomyocytes, cellules musculaires, hématopoïétiques ou neuronales. Le tissu adipeux apparaît donc comme un tissu complexe composé de cellules dont la nature et les potentiels de différenciation varient en fonction de leur localisation ou de l'environnement physiologique ou pathologique, et ces différentes sous populations peuvent interagir entre elles par le biais de sécrétions paracrines. Le tissu adipeux est donc un tissu hétérogène et plastique, facile à prélever, qui pourrait représenter une source potentielle de cellules dont l'utilisation en thérapie cellulaire semble prometteuse

Theoretical inflammation model using ALife technics

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The oral organ: A new vision of the mouth as a whole for a gerophysiological approach to healthy aging

International audienceThis article brings a new perspective on oral physiology by presenting the oral organ as an integrated entity within the entire organism and its surrounding environment. Rather than considering the mouth solely as a collection of discrete functions, this novel approach emphasizes its role as a dynamic interphase, supporting interactions between the body and external factors. As a resilient ecosystem, the equilibrium of mouth ecological niches is the result of a large number of interconnected factors including the heterogeneity of different oral structures, diversity of resources, external and internal pressures and biological actors. The manuscript seeks to deepen the understanding of age-related changes within the oral cavity and throughout the organism, aligning with the evolving field of gerophysiology. The strategic position and fundamental function of the mouth make it an invaluable target for early prevention, diagnosis, treatment, and even reversal of aging effects throughout the entire organism. Recognizing the oral cavity capacity for sensory perception, element capture and information processing underscores its vital role in continuous health monitoring. Overall, this integrated understanding of the oral physiology aims at advancing comprehensive approaches to the oral healthcare and promoting broader awareness of its implications on the overall well-being

Characterization and Safety Profile of a New Combined Advanced Therapeutic Medical Product Platelet Lysate-Based Fibrin Hydrogel for Mesenchymal Stromal Cell Local Delivery in Regenerative Medicine

Adipose-derived mesenchymal stromal cells (ASC) transplant to recover the optimal tissue structure/function relationship is a promising strategy to regenerate tissue lesions. Because filling local tissue defects by injection alone is often challenging, designing adequate cell carriers with suitable characteristics is critical for in situ ASC delivery. The aim of this study was to optimize the generation phase of a platelet–lysate-based fibrin hydrogel (PLFH) as a proper carrier for in situ ASC implantation and (1) to investigate in vitro PLFH biomechanical properties, cell viability, proliferation and migration sustainability, and (2) to comprehensively assess the local in vivo PLFH/ASC safety profile (local tolerance, ASC fate, biodistribution and toxicity). We first defined the experimental conditions to enhance physicochemical properties and microscopic features of PLFH as an adequate ASC vehicle. When ASC were mixed with PLFH, in vitro assays exhibited hydrogel supporting cell migration, viability and proliferation. In vivo local subcutaneous and subgingival PLFH/ASC administration in nude mice allowed us to generate biosafety data, including biodegradability, tolerance, ASC fate and engraftment, and the absence of biodistribution and toxicity to non-target tissues. Our data strongly suggest that this novel combined ATMP for in situ administration is safe with an efficient local ASC engraftment, supporting the further development for human clinical cell therapy