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.

Magnetic nanoparticles in regenerative medicine: what of their fate and impact in stem cells?

“…1G). Functionalized nanoparticles can also be used to activate specific cell surface mechanoreceptors and initiate their signaling response [98,99] (Fig. 1H).…”

Magnetogenetics: remote activation of cellular functions triggered by magnetic switches

“…For example, it was shown that classical iron oxide microparticles which are commercially available (2.8 μm; Dynabead) coated with wheat germ agglutinin (WGA) can generate 30 pN per microparticle under a rotating DC field of 200 mT. 33 Other big magnetic actuators, such as 250 nm magnetite MNPs were capable of activating intracellular pathways in a neuronal cell line 34 and in mesenchymal cells 35 by generating mechanical forces of about 10 -12 pN. Moreover, a positive correlation between size and exerted mechanical force was reported for a set of magnetite particles ranging from 250 nm to 2.7 μm in diameter, which could generate mechanical forces between 0.2 to 38.9 pN per particle depending on their size.…”

Wnt signaling activation: targets and therapeutic opportunities for stem cell therapy and regenerative medicine

“…Rotherham et al showed that remote activation of UM206 by MNPs with magnetic field stimulation was feasible to activate Wnt/β-catenin pathway, promoting bone formation in chicks, and dopaminergic marker expression in rats' neurons 41,42 . This makes Wnt signaling an important therapeutic target for neurogenerative disease such as Parkinson's disease 42,43 . c. Recombinant Norrin Norrin is another cysteine-rich secreted protein, encoded by NDP gene, that binds with high affinity and specificity to FZD4 and LRP5/6, activate Wnt/β-catenin 44 , and has angiogenic and neuroprotective properties 45,46 .…”