Immortalization of Mesenchymal Stem Cells for Application in Regenerative Medicine and Their Potential Risks of Tumorigenesis

Regenerative medicine utilizes stem cells to repair damaged tissues by replacing them with their differentiated cells and activating the body's inherent regenerative abilities. Mesenchymal stem cells (MSCs) are adult stem cells that possess tissue repair and regenerative capabilities and immunomodulatory properties with a much lower risk of tumorigenicity, making them a focus of numerous clinical trials worldwide. MSCs primarily exert their therapeutic effects through paracrine effects via secreted factors, such as cytokines and exosomes. This has led to increasing interest in cell-free therapy, where only the conditioned medium (also called secretome) from MSC cultures is used for regenerative applications. However, MSCs face certain limitations, including cellular senescence, scarcity, donor heterogeneity, complexity, short survival post-implantation, and regulatory and ethics hurdles. To address these challenges, various types of immortalized MSCs (ImMSCs) capable of indefinite expansion have been developed. These cells offer significant promise and essential tools as a reliable source for both cell-based and cell-free therapies with the aim of translating them into practical medicine. However, the process of immortalization, often involving the transduction of immortalizing genes, poses potential risks of genetic instability and resultant malignant transformation. Cell-free therapy is particularly attractive, as it circumvents the risks of tumorigenicity and ethical concerns associated with live cell therapies. Rigorous safety tests, such as monitoring chromosomal abnormalities, are critical to ensure safety. Technologies like inducible or suicide genes may allow for the controlled proliferation of MSCs and induce apoptosis after their therapeutic task is completed. This review highlights recent advancements in the immortalization of MSCs and the associated risks of tumorigenesis.