Magnetic Mechanoactivation of Wnt Signaling Augments Dopaminergic Differentiation of Neuronal Cells

Abstract

Wnt signaling is a key developmental pathway that regulates dopaminergic progenitor cell proliferation and differentiation during neuronal development. This makes Wnt signaling an important therapeutic target for neurodegenerative conditions such as Parkinson's disease. Wnt signaling can be modulated using peptides such as UM206, which bind to the Wnt receptor Frizzled. Previous work has demonstrated remote activation of the Wnt pathway through Frizzled using peptide‐functionalized magnetic nanoparticles (MNPs) with magnetic field stimulation. Using this technology, Wnt signaling is remotely activated in the neuronal cell line SH‐SY5Y, and the phenotypic response to stimulation is assessed. Results indicate β‐catenin translocalization and activation of TCF/LEF responsive transcription in response to MNP and magnetic fields, which result in dopaminergic marker expression when synergistically combined with differentiation factors retinoic acid and the phorbol ester phorbol 12‐myristate 13‐acetate. This approach is translated into ex vivo postnatal rat brain slices modeling the developing nigrostriatal pathway. Dopaminergic marker expression is maintained in MNP‐labeled SH‐SY5Y cells after injection and magnetic stimulation. These results demonstrate the translational value of remote control of signal transduction for controlling neuronal precursor cell behavior and highlight the potential applications for controlled cell differentiation as part of cell therapies for neurodegenerative disease.

Magnetogenetics as a Promising Tool for Controlling Cellular Signaling Pathways

“…Expanding upon these insights, magnetogenetics' capacity to direct cell fate has been further demonstrated in studies involving mesenchymal stem cells (MSCs) equipped with superparamagnetic iron oxide nanoparticles aimed at the Wnt receptor Frizzled (Figure 7 A-C). These studies revealed that pulsed magnetic fields could drive osteogenic [232] and neuronal differentiation [238], instigating Wnt signaling [239] and β-catenin translocation [232,240]. This finding underscores magnetogenetics' capability to navigate cell destiny.…”

Immobilization of Wnt Fragment Peptides on Magnetic Nanoparticles or Synthetic Surfaces Regulate Wnt Signaling Kinetics

“…Although this study is not the first one published in this area, it is the first mechanistic study to be performed and provided an interesting and important insight into the effect that the peptide presentation method had on downstream Wnt signaling activity. The current study also provided a solid foundation for other published works in this area involving magnetic activation of Wnt, which focused on in vitro signaling in human mesenchymal stem cells (hMSCs), neuronal differentiation of SH-SY5Y and an ex vivo bone tissue engineering model using hMSCs injected into chicken femurs respectively [ 27 , 28 , 29 ]. Recent work has also shown that the nanomagnetic activation approach and immobilized platforms are promising tools that are readily translatable as platforms for drug discovery or stem cell niche recreation, or for tissue engineering applications [ 23 , 25 , 30 ].…”

Curved Magnetic Hydrogels for Understanding Cancer Initiation

“…It was referred by the authors that the same effect was not observed for other cancer types such as human gastrointestinal stromal tumor GIST-T1, although other studies have obtained promising therapeutic responses with magnetic stimulation for neuroblastoma or even neurodegenerative diseases. , The observed downregulation of stemness associated with genes OCT4 and SOX4 in response to magnetic field stimulation may be mediated by mechanotransduction pathways that interface with transcriptional regulation. Previous studies have shown that magnetic fields, in particular oscillatory magnetic fields, can activate intracellular signaling cascades such as the MAPK/ERK pathway, known to influence cell fate decisions and differentiation processes.…”

“… Additionally, magnetic mechanoactivation has been demonstrated to modulate Wnt/β-catenin signaling through remote stimulation of Frizzled receptors using magnetic nanoparticles. Given that Wnt signaling plays a pivotal role in maintaining stemness and regulating OCT4 expression, it is possible that magnetic stimulation disrupts this pathway, thereby promoting differentiation. Furthermore, magnetogenetic approaches have revealed that magnetic fields can influence gene expression by altering cytoskeletal tension and nuclear architecture, which are upstream regulators of transcriptional machinery.…”