Alzheimer’s disease (AD) is a chronic, mild cognitive deficit which is currently suffered by millions of people.1, 2 It is caused by synaptic failure and excessive accumulation of misfolded proteins. To date, almost all advanced clinical trials on specific AD-related pathways have failed mostly due to a large number of neurons lost in the brain of patients with AD. Also, currently available drug candidates intervene too late, which brings heavy burden to public administration and caregivers.3
The brain requires multiple cell types, such as neurons, astrocytes, microglia, oligodendrocytes, and endothelial cells, working in concert to perform activities of day-to-day life.4 Neural stem cells (NSCs) are responsible for the production of all nerve cell types during development of multiple cells. The use of nanomaterials to regulate the differentiation of NSCs offers an interesting approach with promising therapeutic potential against AD.5-7 Chirality is a unifying property of circularly polarized light (CPL) and nearly all molecules forming living cells.8, 9
Here, we show that the differentiation of NSCs to neurons can be accelerated by chiral photons when DNA-bridged chiral assemblies of gold nanoparticles are tightly entangled with the cytoskeletal fibers (Figure 1).10 When irradiated with CPL (532nm, 50 Hz), 70.7% of stem cells differentiated into neuronal cells within 5 days. Plasmonic force calculations indicate that the nanoparticle assemblies exert a CPL-dependent mechanical force at about 10 nN on cytoskeleton. The mechanism of this phenomenon includes three essential elements (1) chiroptically active nanoparticle assemblies enter the cells and change their conformation enmeshing the DNA-brodged NPs with actin network; (2) circularly polarized light exert polarization-dependent force on the nanoassemblies and, thus, on nanofibers; (3) periodic mechanical deformation of the cytoskeleton under 50 Hz pulsed light stimulate NSC differentiation into neuronal phenotype. The large difference of neurite length, global gene expression analysis, differentiation markers, and large difference between RCP, LCP, and LP light illumination protocols verify the mechanism and demonstrate that circular polarization can be utilized to direct stem cell development along the desirable neuronal pathway.
Furthermore, it has been found that implantation of CPL-differentiated NSCs substantially reduced the formation of Alzheimer plaques by more than 70%, and lead to a successful recovery in their pathologic behavior. The discoveries provide a mechanistic framework for the further exploration of the biological effects of CPL for different types of cells.
Figure 1. (a) Schematic illustration of differentiation of NSCs with CPL after daily incubation with C30(D)S5-C20(L) for 5 days. Two-photon luminescence images of α-actinin-1 for cytoskeleton in NSCs after incubated with (b) C30(D)S5-C20(L), or (c) C30(L)S5-C20(D) for 4 h each day, and then exposed to polarity-optimized CPL illumination protocol (RRR-LL for C30(D)S5-C20(L); LLL-RR for C30(L)S5-C20(D)) (50 μJ/pulse, 50 Hz, 5 min) for 5 days, Red: α-actinin-1 for cytoskeleton, White: C30(D)S5-C20(L) or C30(L)S5-C20(D) nanoassemblies, Blue: DAPI for the nuclei. Scale bar, 10 μm.
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10. Qu, A. H. et al. Circularly Polarized Light Transduced by Chiral Nanoassemblies Stimulates Differentiation of Stem Cells. Nature Biomedical Engineering. (2020) Accepted.