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Stem Cell Reports. 2015 Dec 8;5(6):988-995. doi: 10.1016/j.stemcr.2015.10.014. Epub 2015 Nov 19.

Metformin Acts on Two Different Molecular Pathways to Enhance Adult Neural Precursor Proliferation/Self-Renewal and Differentiation.

Author information

1
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.
2
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
3
Department of Pediatrics and Medicine, Johns Hopkins Medical School, Baltimore, MD 21287, USA.
4
Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
5
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.
6
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.
7
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.

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.

PMID:
26677765
PMCID:
PMC4682208
DOI:
10.1016/j.stemcr.2015.10.014
[Indexed for MEDLINE]
Free PMC Article

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