Abstract
Mesenchymal stem cells (MSCs) have attracted tremendous research interest due to their ability to repair tissues and reduce inflammation when implanted into a damaged or diseased site. These therapeutic effects have been largely attributed to the collection of biomolecules they secrete (i.e., their secretome). Recent studies have provided evidence that similar effects may be produced by utilizing only the secretome fraction containing extracellular vesicles (EVs). EVs are cell-derived, membrane-bound vesicles that contain various biomolecules. Due to their small size and relative mobility, they provide a stable mechanism to deliver biomolecules (i.e., biological signals) throughout an organism. The use of the MSC secretome, or its components, has advantages over the implantation of the MSCs themselves: (i) signals can be bioengineered and scaled to specific dosages, and (ii) the nonliving nature of the secretome enables it to be efficiently stored and transported. However, since the composition and therapeutic benefit of the secretome can be influenced by cell source, culture conditions, isolation methods, and storage conditions, there is a need for standardization of bioprocessing parameters. This review focuses on key parameters within the MSC culture environment that affect the nature and functionality of the secretome. This information is pertinent to the development of bioprocesses aimed at scaling up the production of secretome-derived products for their use as therapeutics.
Highlights
Mesenchymal stem cells (MSCs) are unspecialized cells that can be isolated from various tissues within the body including bone marrow, adipose, dermal, umbilical cord blood, and synovial fluid [1,2,3]
A cell population isolated from these tissues is considered to contain primarily MSCs if it meets the following minimum criteria defined by the International Society for Cellular Therapy: (i) the cell population must be plastic-adherent; (ii) ≥95% of the cell population needs to express the surface antigens CD105, CD73, and CD90 and ≤2% may express CD45, CD34, CD14 or CD11b, CD79α or CD19, and HLA-DR; and (iii) the cells need to be able to differentiate to bone, fat, and cartilage fates in vitro [4]
While not necessarily directly reflective of the oxygen levels to which the cells are exposed, conditioning of MSCs at headspace oxygen concentrations of 1–5%, often referred to as hypoxic culture conditions, is employed as a less extreme method than anoxia to induce the activation of survival pathways and the secretion of products that may adapt the cells to their stressed environment [24]
Summary
Mesenchymal stem cells (MSCs) are unspecialized cells that can be isolated from various tissues within the body including bone marrow, adipose, dermal, umbilical cord blood, and synovial fluid [1,2,3]. The focus of many clinical trials has been to evaluate the therapeutic effects of the factors and molecules produced by mesenchymal stem cells, rather than integration of the cells themselves These secreted factors and molecules, collectively referred to as the MSC “secretome,” are hypothesized to upregulate endogenous repair and immunomodulation mechanisms [9]. While much work has been done to understand how the cells themselves change in response to environmental factors such as oxygenation, mechanical forces, and chemical stimuli, considerably less work has focused on the effect of these factors on resultant secretome profiles Such studies would enable secretome optimization for specific applications and provide an essential foundation for larger-scale production. This review outlines the therapeutic products that can be obtained from MSCs and important culture parameters that need to be considered for the scalable production and clinical translation of the MSC secretome
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