Abstract
Mesenchymal stem/stromal cells (MSC) remain a promising tool for regenerative medicine as the efficacy of MSC-based cell therapy has been demonstrated for a broad spectrum of indications. Their therapeutic potency is mainly associated with their ability to secrete multiple factors critical for tissue regeneration. Due to comparable effects along with superior safety MSC conditioned medium (MSC-CM) containing a complex of MSC-secreted products is considered a reasonable alternative to cell therapy. However, the lack of standards regulating bioprocessing, use of proper auxiliary materials, and quality control complicates the development of MSC secretome-based therapeutics. In this study, we suggested several approaches addressing these issues. We manufactured 36 MSC-CM samples based on different xeno-free serum-free chemically defined media (DMEM-LG or MSC NutriStem® XF) using original protocols and considered total concentrations of regeneration-associated paracrine factors secreted by human adipose-derived MSC at each time-point of conditioning. Using regression analysis, we retrospectively predicted associations between concentrations of several components of MSC-CM and its biological activity to stimulate human dermal fibroblast and endothelial cell migration in vitro as routine examples of potency assays for cell-based products. We also demonstrated that the cell culture medium might affect MSC-CM biological activity to varying degrees depending on the potency assay type. Furthermore, we showed that regression analysis might help to overcome donor variability. The suggested approaches might be successfully applied for other cell types if their secretome was shown to be promising for application in regenerative medicine.
Highlights
The application of mesenchymal stem/stromal cells (MSC) in regenerative medicine has been intensively studied in hundreds of clinical trials as these cells represent a promising source of multipotent adult stem and progenitor cells for cell therapy and tissue engineering [1,2]
MSC secretome is suggested as a novel cell-free medicinal product that can recapitulate the beneficial effects of MSC and has various advantages in overcoming the limitations and risks associated with cell-based therapy [33,34]
Mr ocl.oSncci.e2n01tr9a, 2t0io, 1n6s5.6 Surprisingly, we showed that Angpt-1 concentration was the most p6ootef n16t predictor of human dermal fibroblast migration stimulated by MSC conditioned medium (MSC-CM)
Summary
The application of mesenchymal stem/stromal cells (MSC) in regenerative medicine has been intensively studied in hundreds of clinical trials as these cells represent a promising source of multipotent adult stem and progenitor cells for cell therapy and tissue engineering [1,2]. MSC-CM that contains cell-secreted products has demonstrated therapeutic benefit for the treatment of ischemic diseases such as myocardial infarction, stroke and acute and chronic hindlimb ischemia, neurodegenerative diseases, spinal cord injury, alopecia, acute and chronic wounds, acute liver injury/failure, lung injury, periodontal tissues injury, male infertility, soft tissue and bone defects [18,19,20,21,22,23]. MSC-secreted extracellular vesicles that carry regulatory noncoding RNAs were used as therapeutic agents to stimulate tissue regeneration [28,29,30,31,32]. MSC secretome is suggested as a novel cell-free medicinal product that can recapitulate the beneficial effects of MSC and has various advantages in overcoming the limitations and risks associated with cell-based therapy [33,34]
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