Cellular expansion of MSCs: Shifting the regenerative potential

Abstract

Mesenchymal‐derived stromal or progenitor cells, commonly called “MSCs,” have attracted significant clinical interest for their remarkable abilities to promote tissue regeneration and reduce inflammation. Recent studies have shown that MSCs' therapeutic effects, originally attributed to the cells' direct differentiation capacity into the tissue of interest, are largely driven by the biomolecules the cells secrete, including cytokines, chemokines, growth factors, and extracellular vesicles containing miRNA. This secretome coordinates upregulation of endogenous repair and immunomodulation in the local microenvironment through crosstalk of MSCs with host tissue cells. Therapeutic applications for MSCs and their secretome‐derived products often involve in vitro monolayer expansion. However, consecutive passaging of MSCs significantly alters their therapeutic potential, inducing a broad shift from a pro‐regenerative to a pro‐inflammatory phenotype. A consistent by‐product of in vitro expansion of MSCs is the onset of replicative senescence, a state of cell arrest characterized by an increased release of proinflammatory cytokines and growth factors. However, little is known about changes in the secretome profile at different stages of in vitro expansion. Some culture conditions and bioprocessing techniques have shown promise in more effectively retaining the pro‐regenerative and anti‐inflammatory MSC phenotype throughout expansion. Understanding how in vitro expansion conditions influence the nature and function of MSCs, and their associated secretome, may provide key insights into the underlying mechanisms driving these alterations. Elucidating the dynamic and diverse changes in the MSC secretome at each stage of in vitro expansion is a critical next step in the development of standardized, safe, and effective MSC‐based therapies.

Therapeutic Perspectives for Inflammation and Senescence in Osteoarthritis Using Mesenchymal Stem Cells, Mesenchymal Stem Cell-Derived Extracellular Vesicles and Senolytic Agents

“…Senescent MSCs, therefore, have reduced therapeutic potential and may even be harmful if transplanted into patients. We have also observed that during the expansion of MSCs isolated from adipose tissue and bone marrow, accumulation of senescent cells occurs [228].…”

Dual impacts of mesenchymal stem cell-derived exosomes on cancer cells: unravelling complex interactions

“…They also cause MHC class II + macrophage differentiation with increased l‐arginase activity and secretion of IL‐10 in the tumor microenvironment (Biswas et al 2019). It is important to note that despite the high durable response rates to immunotherapies, a large percentage of patients do not respond due to primary, adaptive, or acquired resistance to immune therapies (Miclau et al 2023). In the tumor immunological microenvironment, MSC‐Exos can play a contrasting dual immunomodulatory role by altering the activities of various immune cell types, including NK cells, M‐MDSCs, and B‐ and T‐lymphocytes (Biswas et al 2019; Zhou et al 2021).…”

“…The term “secretome” describes the group of molecules that cells secrete, comprising lipids, proteins, nucleic acids, and other bioactive compounds (Daneshmandi et al 2020). The diversity found in the secretome of EVs showcases the distinctive roles and conditions exhibited by the donor cells (Miclau et al 2023). The diverse biomolecules carried by EVs also reflect the functional diversity of these vesicles (Driscoll and Patel 2019; Walker et al 2019).…”

Tricarboxylic Acid Cycle Metabolite-Coordinated Biohydrogels Augment Cranial Bone Regeneration Through Neutrophil-Stimulated Mesenchymal Stem Cell Recruitment and Histone Acetylation-Mediated Osteogenesis

“…Large bone defects are often associated with non- or delayed-union disease, which is primarily ascribed to the inadequate quantity of MSCs and the limited osteoinductive ability of the resident MSCs in the lesional milieu. Therefore, tissue engineering strategies involving the delivery of ex vivo MSCs with an osteoinductive ability from carriers have been developed to promote bone development and repair. , Nevertheless, the manipulation of exogenous MSCs for clinical application still faces formidable challenges due to their inadequate in vitro expansion, which shifts the regenerative potential in long cultures, as well as their high cost, safety concerns, and limited in vivo survival rates at damaged sites. − …”