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Low-Field Magnetic Stimulation Accelerates the Differentiation of Oligodendrocyte Precursor Cells via Non-canonical TGF-β Signaling Pathways Natalia Dolgova 1,2,3 & Zelan Wei 1 & Brandon Spink 1 & Le Gui 1 & Qinyun Hua 1 & Davin Truong 1 & Zhen Zhang 4 & Yanbo Zhang 1,5 Received: 3 June 2020 / Accepted: 30 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract Demyelination and oligodendrocyte loss are characteristic changes in demyelinating disorders. Low-field magnetic stimulation (LFMS) is a novel transcranial neuromodulation technology that has shown promising therapeutic potential for a variety of neuropsychiatric conditions. The cellular and molecular mechanisms of magnetic stimulation remain unclear. Previous studies mainly focused on the effects of magnetic stimulation on neuronal cells. Here we aimed to examine the effects of a gamma frequency LFMS on the glial progenitor cells. We used rat central glia-4 (CG4) cell line as an in vitro model. CG4 is a bipotential glial progenitor cell line that can differentiate into either oligodendrocyte or type 2-astrocyte. The cells cultured in a defined differentiation media were exposed to a 40-Hz LFMS 20 min daily for five consecutive days. We found that LFMS transiently elevated the level of TGF-β1 in the culture media in the first 24 h after the treatment. In correlation with the TGF-β1 levels, the percentage of cells possessing complex branches and expressing the late oligodendrocyte progenitor marker O4 was increased, indicating the accelerated differentiation of CG4 cells towards oligodendrocyte in LFMS-treated cultures. LFMS increased phosphorylation of Akt and Erk1/2 proteins, but not SMAD2/3. TGF-β1 receptor I specific inhibitor LY 364947 partially suppressed the effects of LFMS on differentiation and on levels of pAkt and pErk1/2, indicating that LFMS enhances the differentiation of oligodendrocyte progenitor cells via activation of non-canonical TGF-β-Akt and TGF-β-Erk1/2 pathways but not the canonical SMAD pathway. The data from this study reveal a novel mechanism of magnetic stimulation as a potential therapy for demyelination disorders. Keywords LFMS . Oligodendrocyte progenitor cell . Differentiation . TGF-β . Akt . Erk1/2

Introduction Natalia Dolgova and Zelan Wei contributed equally to this work. * Yanbo Zhang [email protected] 1

Department of Psychiatry, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada

2

Department of Geological Sciences, College of Arts and Sciences, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E2, Canada

3

Department of Biochemistry, Microbiology, and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada

4

Department of Ultrasound, The First Hospital of China Medical University, Shenyang 110001, Liaoning, China

5

Present address: Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2B7, Canada

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