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Metformin promotes neuronal differentiation and neurite outgrowth through AMPK activation in human bone marrow–mesenchymal stem cells

Metformin is an AMP‐activated kinase (AMPK) activator that plays a role in glucose energy metabolism and cell protection. It is widely used to treat several diseases, including type 2 diabetes, cardiovascular diseases, cancer, and metabolic diseases. In this study, we investigated whether AMPK activation upon treatment with metformin may promote neurite outgrowth during the progression of neuronal differentiation in human bone marrow–mesenchymal stem cells (hBM–MSCs). Differentiation of metformin‐treated MSCs (Met‐MSCs to Met‐diMSCs) in the neuronal induction media resulted in an increase in the number of differentiated cells in a metformin concentration dependent manner. The differentiation rate reached its maximum at 3 H after the initial treatment with neuronal induction media. At 3 H of induction, the neurite length increased significantly in Met‐diMSCs as compared with control cells without metformin treatment (diMSCs). diMSCs showed a significant increase in the expression of neuronal‐specific marker genes; however, the expression of dendrite‐specific markers MAP‐2 and Tuj‐1 was significantly increased in Met‐diMSCs as compared to diMSCs, as confirmed by immunoblotting. This effect was abolished upon treatment with the AMPK inhibitor, compound C, as evident by quantitative PCR, immunoblotting, and immunocytochemical staining. Thus, metformin treatment promotes neuronal differentiation and neurite outgrowth in hBM–MSCs through AMPK activation.