Umbilical cord mesenchymal stromal cells (UC-MSCs) are emerging as leading stem cells in regenerative medicine due to their high proliferative capacity, potent immunomodulatory effects, and non-invasive collection. However, the absence of standardized guidance on optimal passage number and tissue-specific characterization criteria limits clinical translation, raising concerns about variability in potency, genomic stability, and safety. This review synthesizes evidence on how in vitro passaging alters UC-MSC properties, including purity, proliferation, senescence, genomic integrity, differentiation, and immunomodulation. Preclinical data suggest that UC-MSCs tolerate extended passaging better than MSCs derived from other sources, with several functional attributes preserved up to later passages. Clinical evidence indicates that early to middle passages (P3–P5) achieve the best balance between scalability and therapeutic efficacy. We further propose an updated immunophenotypic framework incorporating tissue-specific positive and negative markers to enhance clinical-grade characterization. Establishing harmonized passage guidelines and potency assays is essential to maximize reproducibility, safety, and the translational potential of UC-MSC therapies.
Fang et al. (Sun,) studied this question.