Stem Cell Therapies for Gastrointestinal and Liver Diseases: Translational Barriers, Clinical Heterogeneity, and Future Directions.

Gastrointestinal and liver diseases remain major contributors to global morbidity and mortality, with limited options for curative or regenerative treatment. Innovative cell-based platforms for liver regeneration and treatment include advanced therapy medicinal products (ATMPs) based on mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), and organoids produced by them, while cell-free systems like extracellular vesicles (EVs) offer a new approach to restore tissue function and homeostasis. This review summarizes key advances from 2020 to 2025 in the translational development of these platforms. MSCs have achieved clinical validation in perianal Crohn's disease and show encouraging antifibrotic and immunomodulatory effects in cirrhosis and acute-on-chronic liver failure. iPSC and iPSC-derived organoids now enable disease modeling and, in early trials, have shown direct epithelial repair. Emerging cell-free approaches based on EVs promise safer, scalable products. Despite rapid progress, challenges remain in potency standardization, manufacturing, and long-term efficacy assessment. International harmonization through the EMA, FDA, and PMDA frameworks is accelerating the translation of stem cell-based advanced therapy medicinal products. The integration of bioengineering, data science, and ethical governance will determine whether these regenerative approaches evolve into accessible standard-of-care interventions for gastrointestinal and hepatic diseases.