title: Wnts enhance neurotrophin-induced neuronal differentiation in adult bone-marrow-derived mesenchymal stem cells via canonical and noncanonical signaling pathways.
abstract: Wnts were previously shown to regulate the neurogenesis of neural stem or progenitor cells. Here, we explored the underlying molecular mechanisms through which Wnt signaling regulates neurotrophins (NTs) in the NT-induced neuronal differentiation of human mesenchymal stem cells (hMSCs). NTs can increase the expression of Wnt1 and Wnt7a in hMSCs. However, only Wnt7a enables the expression of synapsin-1, a synaptic marker in mature neurons, to be induced and triggers the formation of cholinergic and dopaminergic neurons. Human recombinant (hr)Wnt7a and general neuron makers were positively correlated in a dose- and time-dependent manner. In addition, the expression of synaptic markers and neurites was induced by Wnt7a and lithium, a glycogen synthase kinase-3β inhibitor, in the NT-induced hMSCs via the canonical/β-catenin pathway, but was inhibited by Wnt inhibitors and frizzled-5 (Frz5) blocking antibodies. In addition, hrWnt7a triggered the formation of cholinergic and dopaminergic neurons via the non-canonical/c-jun N-terminal kinase (JNK) pathway, and the formation of these neurons was inhibited by a JNK inhibitor and Frz9 blocking antibodies. In conclusion, hrWnt7a enhances the synthesis of synapse and facilitates neuronal differentiation in hMSCS through various Frz receptors. These mechanisms may be employed widely in the transdifferentiation of other adult stem cells.
authors.affiliation: Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hung-Li
authors.initials: HL
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Biomedical Materials and Engineering, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wing-Ping
authors.initials: WP
authors.lastname: Deng
authors.affiliation: Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan; McLean Imaging Center, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, United States of America; Center for Nano-Tissue Engineering and Image Research, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Wen-Fu Thomas
authors.initials: WF
authors.lastname: Lai
authors.affiliation: Center for Nano-Tissue Engineering and Image Research, Taipei Medical University Hospital, Taipei, Taiwan; Department of Neurosurgery, Taipei Medical University-Shuan-Ho Hospital, Taipei, Taiwan.
authors.forename: Wen-Ta
authors.initials: WT
authors.lastname: Chiu
authors.affiliation: Department of Orthopedics, Taipei County Hospital, Taipei, Taiwan.
authors.forename: Charn-Bing
authors.initials: CB
authors.lastname: Yang
authors.affiliation: Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Tsai
authors.affiliation: Bioresource Collection and Research Center, Food Industry Research and Development Institute, Hsinchu, Taiwan.
authors.forename: Shiaw-Min
authors.initials: SM
authors.lastname: Hwang
authors.affiliation: Department of Psychiatry and The Brain Institute, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Perry F
authors.initials: PF
authors.lastname: Renshaw
mesh_terms: D000368:Aged; D001854:Bone Marrow Cells / Q000166:cytology; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D008875:Middle Aged; D009414:Nerve Growth Factors / Q000378:metabolism*; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction; D016704:Synapsins / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D009414:Nerve Growth Factors; D016704:Synapsins; D051153:Wnt Proteins; D048031:JNK Mitogen-Activated Protein Kinases