Abstract
In the last decades, it has been demonstrated that the regenerative therapeutic efficacy of mesenchymal stromal cells is primarily due to the secretion of soluble factors and extracellular vesicles, collectively known as secretome. In this context, our work described the preparation and characterization of a freeze-dried secretome (Lyosecretome) from adipose tissue-derived mesenchymal stromal cells for the therapy of equine musculoskeletal disorder. An intraarticular injectable pharmaceutical powder has been formulated, and the technological process has been validated in an authorized facility for veterinary clinical-use medicinal production. Critical parameters for quality control and batch release have been identified regarding (i) physicochemical properties; (ii) extracellular vesicle morphology, size distribution, and surface biomarker; (iii) protein and lipid content; (iv) requirements for injectable pharmaceutical dosage forms such as sterility, bacterial endotoxin, and Mycoplasma; and (v) in vitro potency tests, as anti-elastase activity and proliferative activity on musculoskeletal cell lines (tenocytes and chondrocytes) and mesenchymal stromal cells. Finally, proteins putatively responsible for the biological effects have been identified by Lyosecretome proteomic investigation: IL10RA, MXRA5, RARRES2, and ANXA1 modulate the inflammatory process RARRES2, NOD1, SERPINE1, and SERPINB9 with antibacterial activity. The work provides a proof-of-concept for the manufacturing of clinical-grade equine freeze-dried secretome, and prototypes are now available for safety and efficacy clinical trials in the treatment of equine musculoskeletal diseases
Highlights
Musculoskeletal disorders (MSDs) have an extensive and growing impact representing a major health problem worldwide
Three different equine AD-Mesenchymal Stem/Stromal Cells (MSCs) lines from the biobank meet all the requirements for clinical use as all the steps were made according to ISO 9001:2018 clinical grade
Following the Biological processes, Molecular tions, and Protein families that emerged from network analysis, as well as the Functions, and Protein families that emerged from network analysis, as well as the therapeutic properties observed, we focused ourwe attention onour proteins involved in inflamLyosecretome therapeutic properties observed, focused attention on proteins inmatory processes and response to a bacterium
Summary
Musculoskeletal disorders (MSDs) have an extensive and growing impact representing a major health problem worldwide. The understanding of these diseases and the control on their progression has not yet been achieved; different therapeutic approaches are being investigated to prevent the disorders or to promote recovery and/or regeneration of the musculoskeletal system, including muscles, bones, and joints [1,2]. In the veterinary field, many clinical applications of cell-based therapies have been described, starting from the early 2000s with the first application of MSCs on the equine model [5,6]. Despite the considerable amount of data suggesting the safety and efficacy of MSCs in experimental animal models and preclinical studies, cell-based therapies are not yet routinely applied in the clinic [7,8,9,10]. The therapeutic application of MSCs has known a paradigm shift: Nowadays, their engraftment, proliferation, and differentiation properties are not considered key features of their therapeutic abilities
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