Recent Advances in Stem Cell-Based Ex Vivo Cultured Red Blood Cell Production and Clinical Perspectives (2010∼2025)

This review provides a comprehensive overview of the advances in cultured red blood cell (cRBC) production technologies, their clinical applicability, and the underlying biological mechanisms, based on the key literature published between 2010 and 2025.Hematopoietic stem cell-derived cRBC production has several physiological advantages, including a high degree of maturation and expression of adult-type hemoglobin.On the other hand, limitations in proliferative capacity pose significant challenges for large-scale manufacturing.In contrast, induced pluripotent stem cells can proliferate indefinitely and show promise in generating rare blood types.Nevertheless, several technical challenges remain unresolved, including low differentiation efficiency, suboptimal enucleation rates, and the production of immature erythroid cells.Recent advances have focused on technical improvements, including the automation of culture systems, the utilization of bioreactors, the development of serum-free media, and differentiation strategies to enhance the enucleation efficiency.Some studies have reported production levels approaching transfusion-scale units and the generation of mature erythrocytes at rates exceeding 60%.From a clinical perspective, cRBCs have potential for personalized transfusion strategies targeting patients with rare blood types, individuals with alloantibodies, and those requiring chronic transfusions.The RESTORE clinical trial conducted in the United Kingdom is considered the first successful transfusion of cRBCs in humans.In conclusion, the production of cRBCs from stem cells represents a transformative approach with the potential to redefine transfusion medicine.Nevertheless, ongoing technological innovation and rigorous validation of clinical efficacy, as well as ethical justification, will be essential for future commercialization.(