Therapeutic applications of mesenchymal/medicinal stem/signaling cells preconditioned with external factors: Are there more efficient approaches to utilize their regenerative potential?

Mesenchymal/medicinal stem/signaling cells (MSCs) have emerged as a promising treatment option for various disorders. However, the donor's age, advanced stage of disease, and prolonged in vitro expansion often diminish the innate regenerative potential of MSCs. Besides that, the absence of MSCs' comprehensive "pre-admission testing" can result in the injection of cells with reduced viability and function, which may negatively affect the overall outcome of MSC-based therapies. It is, therefore, essential to develop effective strategies to improve the impaired biological performance of MSCs. This review focuses on the comprehensive characterization of various methods of external MSCs stimulation (hypoxia, heat shock, caloric restriction, acidosis, 3D culture, and application of extracellular matrix) that augment their medicinal potential. To emphasize the significance of MSCs priming, we summarize the effects of individual and combined preconditioning approaches, highlighting their impact on MSCs' response to either physiological or pathological conditions. We further investigate the synergic action of exogenous factors to maximize MSCs' therapeutic potential. Not to omit the field of tissue engineering, the application of pretreated MSCs seeded on scaffolds is discussed as well.

Rejuvenation of Senescent Mesenchymal Stem Cells to Prevent Age-Related Changes in Synovial Joints.

Mesenchymal/medicinal stem/signaling cells (MSCs), well known for regenerative potential, have been involved in hundreds of clinical trials. Even if equipped with reparative properties, aging significantly decreases their biological activity, representing a major challenge for MSC-based therapies. Age-related joint diseases, such as osteoarthritis, are associated with the accumulation of senescent cells, including synovial MSCs. An impaired ability of MSCs to self-renew and differentiate is one of the main contributors to the human aging process. Moreover, senescent MSCs (sMSCs) are characterized by the senescence-messaging secretome (SMS), which is typically manifested by the release of molecules with an adverse effect. Many factors, from genetic and metabolic pathways to environmental stressors, participate in the regulation of the senescent phenotype of MSCs. To better understand cellular senescence in MSCs, this review discusses the characteristics of sMSCs, their role in cartilage and synovial joint aging, and current rejuvenation approaches to delay/reverse age-related pathological changes, providing evidence from in vivo experiments as well.