Stem cells for hepatic regeneration: Evaluating mechanisms, sources, and clinical outcomes

Despite rapid advances in regenerative medicine, the clinical translation of stem cell-based therapies for end-stage liver disease remains limited. These approaches seek to promote hepatic repair through cell replacement, paracrine signaling, and immunomodulation, but differ substantially in their mechanisms, functional capabilities, and translational readiness. The distinctive contribution of this review is a mechanism-based and translation-oriented framework that links the biological properties of different stem-cell sources to the requirements for clinical application. We critically compare mesenchymal stem cells, embryonic stem cells, induced pluripotent stem cells, hematopoietic stem/progenitor cells, and liver-resident progenitors according to their predominant regenerative mechanisms, differentiation capacity, immunogenicity, safety, manufacturing feasibility, and clinical evidence. Particular attention is given to distinguishing direct hepatocyte replacement from paracrine support and stimulation of endogenous repair, while separating preclinical findings from evidence obtained in human studies. We also examine MSC-derived extracellular vesicles as an emerging cell-free approach and assess how organoid-based differentiation, three-dimensional encapsulation, and scalable bioreactor systems may address limitations in hepatocyte maturation and functional stability. Importantly, hepatocyte-marker expression is distinguished from mature metabolic function when evaluating the therapeutic potential of stem-cell-derived hepatic cells. By integrating these biological and engineering considerations with product heterogeneity, tumorigenic risk, manufacturing reproducibility, and the need for validated, mechanism-linked potency assays, this review identifies the principal barriers to clinical translation. Rather than providing a descriptive catalog of therapeutic platforms, it offers a comparative framework for evaluating how regenerative mechanisms, functional maturity, and manufacturing constraints shape the clinical readiness of stem cell-based strategies for hepatic regeneration.