title: Metformin Acts on Two Different Molecular Pathways to Enhance Adult Neural Precursor Proliferation/Self-Renewal and Differentiation.
abstract: The recruitment of endogenous adult neural stem cells for brain repair is a promising regenerative therapeutic strategy. This strategy involves stimulation of multiple stages of adult neural stem cell development, including proliferation, self-renewal, and differentiation. Currently, there is a lack of a single therapeutic approach that can act on these multiple stages of adult neural stem cell development to enhance neural regeneration. Here we show that metformin, an FDA-approved diabetes drug, promotes proliferation, self-renewal, and differentiation of adult neural precursors (NPCs). Specifically, we show that metformin enhances adult NPC proliferation and self-renewal dependent upon the p53 family member and transcription factor TAp73, while it promotes neuronal differentiation of these cells by activating the AMPK-aPKC-CBP pathway. Thus, metformin represents an optimal candidate neuro-regenerative agent that is capable of not only expanding the adult NPC population but also subsequently driving them toward neuronal differentiation by activating two distinct molecular pathways.
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5G 1X5, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Fatt
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
authors.forename: Karolynn
authors.initials: K
authors.lastname: Hsu
authors.affiliation: Department of Pediatrics and Medicine, Johns Hopkins Medical School, Baltimore, MD 21287, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
authors.forename: Fredric
authors.initials: F
authors.lastname: Wondisford
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1X5, Canada; Department of Physiology, University of Toronto, Toronto, ON M5G 1X5, Canada.
authors.forename: Freda D
authors.initials: FD
authors.lastname: Miller
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1X5, Canada.
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Brain and Mind Research Institute, University of Ottawa, Ottawa, ON K1H 8M5, Canada. Electronic address: jiwang@ohri.ca.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D053687:Adult Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D009687:Nuclear Proteins / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D007004:Hypoglycemic Agents; D009687:Nuclear Proteins; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D008687:Metformin; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; C115015:PKC-3 protein; D011493:Protein Kinase C; D055372:AMP-Activated Protein Kinases