The Influence of GLP-1 Agonists on Human Mesenchymal Stem Cells: A Systematic Review.

BACKGROUND: Glucagon-like peptide-1 receptor agonists, originally developed for managing type 2 diabetes, have gained attention for their weight-reducing and broader biological effects. Among these, their influence on human mesenchymal stem cells remains underexplored, despite the critical role of mesenchymal stem cells in tissue regeneration and secretion of bioactive factors. METHODS: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify and evaluate in vitro studies investigating the effects of glucagon-like peptide-1 receptor agonists and their analogues on human mesenchymal stem cell functions, including proliferation, differentiation, signaling, apoptosis, and tissue-specific applications. Risk of bias was assessed using an adapted Quality Assessment Tool for In Vitro Studies (QUIN) tool. RESULTS: Thirty-eight eligible studies were identified. Glucagon-like-peptide-1 receptor agonist, like native glucagon-like peptide-1, Exendin-4, and Liraglutide, exert context-, dose-, and timing-dependent effects on human mesenchymal stem cells. They modulate proliferation and overall promote osteogenesis while inhibiting adipogenesis. Key pathways, including Wnt/β-catenin, bone morphogenetic protein 2/Smad, phosphoinositide 3-kinase/Akt and protein kinase A, play a role in this. Furthermore, these agents modulate inflammation, reduce apoptosis, and improve stem cell functions even under diabetic or inflammatory conditions. Exendin-4 facilitated tenogenic and insulin-producing cell differentiation, particularly in engineered scaffolds or genetically engineered human mesenchymal stem cells. CONCLUSION: Glucagon-like peptide-1 receptor agonists modulate key pathways in human mesenchymal stem cells to influence survival, differentiation, and metabolic function, suggesting promising therapeutic potential beyond glycemic control. However, heterogeneous experimental designs and limited translational data necessitate further standardized and in vivo research to define clinical applications.