Disease microenvironment preconditioning: An evolving approach to improve therapeutic efficacy of human mesenchymal stromal cells

Despite the tremendous success in preclinical models, the translation of human mesenchymal stromal cells (hMSCs) as a therapy in the clinic is not up to the expectation. Intrinsic factors (age, sex, health status, life style of the donor, source, cellular senescence, and oxidative stress in hMSCs), extrinsic factors (culture system, batch-to-batch variations, choice of biomaterials, cell processing and preservation protocols), and host microenvironment (inflammatory milieu, oxidative stress, and hypoxia in the recipient) compromise the overall therapeutic efficacy of the transplanted hMSCs. In recent times, the approach of 'Disease Microenvironment Preconditioning (DMP)' has garnered attention to overcome the host-associated attributes involved in compromised hMSCs therapeutic potential. In this review, we discuss various approaches of DMP of hMSCs by employing serum and other body fluids obtained from diseased patients/animals and small molecules, including cytokines such as IFN-γ, IL-6, IL-10, IL- β, TGF-β1, IL-1α, IL-1β, TNF-α, HMGB1, IL-17 A, and IL-8 which are associated with disease conditions. DMP strengthens hMSCs ability to adapt/acclimatize and respond more efficiently to the hostile microenvironment they encounter upon transplantation. DMP modulate hMSCs to withstand inflammation, survive under hypoxic and nutrient-deprived conditions, and resist oxidative stress. Evidence from various disease models ranging from cardiovascular and neurodegenerative disorders to autoimmune diseases and tissue injuries supports the role of DMP in improving hMSC survival, integration, and functional efficacy. While the potential of DMP to revolutionize MSC-based therapies is evident, challenges such as standardizing/optimizing protocols for preconditioning is essential. This review synthesizes current advancements in the approach of DMP aiming to propel the area of regenerative medicine.