Extremely low‐frequency electromagnetic field induces neural differentiation of hBM‐MSCs through regulation of (Zn)‐metallothionein‐3

Abstract

Extremely low-frequency electromagnetic field (ELFEMF) can stimulate neural differentiation in human bone marrow-derived mesenchymal cells (hBM-MSCs), and this provides an opportunity for research on neurodegenerative diseases such as Alzheimer's disease (AD). Metallothionein-3 (MT3), an isoform of the metal-binding proteins, metallothioneins, involved in maintaining intracellular zinc (Zn) homeostasis and the deregulation of zinc homeostasis, has separately been implicated in AD. Here, we investigated the effect of ELFEMF-induced neural differentiation of hBM-MSCs on Zn-MT3 homeostatic interaction. Exposure to ELFEMF induced neural differentiation of hBM-MSCs, which was characterized by decreased proliferation and enhanced neural-like morphology. We observed expression of neuronal markers such as β-tubulin3, pleiotrophin, and neurofilament-M at the mRNA level and MAP2 at the protein level. ELFEMF-induced neural differentiation correlated with decreased expression of metal-response element-transcription factor 1 and MT3, as well as decreased intracellular Zn concentration. In addition, upregulation of dihydropyrimidinase-related protein 2 was observed, but there was no change in γ-enolase expression. These data indicate a possible regulatory mechanism for MT3 during neural differentiation. Our findings provide considerable insight into molecular mechanisms involved in neural differentiation, which is useful for developing new treatments for neurodegenerative diseases. Bioelectromagnetics. 38:364-373, 2017. © 2017 Wiley Periodicals, Inc.

The roles of metallothioneins in carcinogenesis

“…Their study found that during this interaction, MT3 expression was downregulated, and the formation of zinc-MT3 complexes was enhanced to maintain zinc homeostasis. A new homeostatic regulatory mechanism was thus discovered, which involved the zinc-MT3 complex and other MT3-interacting proteins to drive neural differentiation, thereby highlighting the potential diagnostic and clinical applications for MT3 in neurodegenerative diseases [ 54 ]. Moreover, Wu et al demonstrated MTs as negative regulators for interleukin (IL)-27-induced type 1 regulatory T cell differentiation [ 55 ].…”

Metallothionein‐I/II expression associates with the astrocyte DNA damage response and not Alzheimer‐type pathology in the aging brain

“…While recent research has primarily focused on enhancing MT‐III as a therapeutic strategy for AD (Aikins et al, ; Roy et al, ), the current study highlights the additional potential of targeting MT‐I/II expression. In summary we demonstrate that MT‐I/II is predominantly expressed by astrocytes in the ageing brain, is associated with the astrocyte DDR and is upregulated in response to oxidative stress in vitro.…”

The Effects of Electromagnetic Fields on Human Health: Recent Advances and Future

“…Neural differentiation of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) may provide an opportunity to restore neural function in AD patients. Some literatures have demonstrated that EMFs can induce hBM-MSCs to differentiate into neural stem cells [93][94][95][96] . One research shows that EMFs combined with drugs may enhance the repair of some brain injuries, and promote the in vivo differentiation of transplanted hBM-MSCs derived from in vitro culture [94] .…”

“…One research shows that EMFs combined with drugs may enhance the repair of some brain injuries, and promote the in vivo differentiation of transplanted hBM-MSCs derived from in vitro culture [94] . Further mechanism research has found that ELF-EMFs can induce the neural differentiation of hBM-MSCs by regulating intracellular level of Zn-metallothionein [93] . In another study, ELF-EMF (50 Hz, 0.4 mT) has been reported to effectively promote the proliferation and differentiation of neural progenitor cells (NPCs) by increasing the level of phosphorylated Akt [97] .…”