Cell-cell fusion and stem cell plasticity: Emerging paradigms in tissue regeneration

Cell-cell fusion is a fundamental biological process contributing to tissue development, homeostasis, and regeneration. Physiological fusion in the placenta, skeletal muscle, bone, and immune system is mediated by tightly regulated fusogens and microenvironmental cues. Dysregulated fusion, however, can lead to pathological outcomes, including malignant cell hybrids and viral syncytia. Stem cell-somatic cell fusion represents both a therapeutic opportunity and a safety concern, as fusion-derived heterokaryons and synkaryons can enhance tissue repair and plasticity while posing risks of genomic instability and unintended fusion events. In this review, we synthesize current knowledge on the molecular mechanisms, tissue-specific fusogens, and regulatory programs governing cell fusion. We also discuss translational strategies for harnessing stem cell fusion in regenerative therapies, highlighting opportunities to maximize repair while minimizing potential risks. Our goal is to provide a unified framework that integrates physiological and pathological perspectives, offering guidance for future research and clinical application.