# The Potential of Visible and Far-Red to Near-Infrared Light in Glaucoma Neuroprotection
## 5 Visible and Far-Red to Near-Infrared Photobiomodulation in Neuronal Differentiation  
Many studies have found that mesenchymal stem cells (MSCs) can be used in the treatment of neurological diseases, including Alzheimer's, spinal cord injury, and stroke; this is because the differentiation of MSCs could be multi-directional and it is regulated in vivo by many factors [50]. However, uncontrolled proliferation and even tumor formation are due to a lack of guidance and regulation; this remains a major safety concern in the use of stem cells for therapeutic intervention. Additionally, in glaucoma, the regenerative potentialities of MSC could be vital in the substitution of damaged RGCs, but their differentiation should be tightly controlled. In the neurological field, photobiomodulation therapy (PBMT) acts on neural cells as a complementary treatment of spinal cord trauma, traumatic brain degeneration/injury, and in the process of peripheral nerve regeneration [38]. Indeed, there is a relationship between the improvement in trophic conditions and a reduction in inflammatory processes; this is closely related to more efficient nervous regeneration, ATP production, enhanced secretion of neural factors, increased vascular network, and collagen synthesis, and it facilitates neural differentiation and regeneration [38; 51] due to the photochemical and photobiological effects of PBM at the cellular level. The potential role of PBM in stimulating cell differentiation has been described in various in vitro human stem cell models. Indeed, a 810 nm wavelength was used to stimulate dental pulp stem cells [52], and red (660 nm) and near-infrared (810 nm) red lights were shown to be more effective than blue and green (415 nm and 540 nm) in inducing a differentiation of human adipose-derived stem cells (hASC) into osteoblasts when they were cultured in an osteogenic medium. In fact, after green/blue stimulation, intracellular calcium and ATP production were lower compared to after the red light, and they were associated with higher level of ROS [53]. Recently, irradiation with a laser light at 808-nm, delivering energy densities from 0 to 10 J/cm\({}^{2}\), has been demonstrated to induce early stage neuronal differentiation rather than glial differentiation in human umbilical cord mesenchymal stem cells [54]. Additionally, neuromodulation is achievable by photostimulation; indeed, when the principal glial cells of peripheral neural system, human Schwann cells, were treated with a diode laser at 810 nm and 50 mW (1 J/cm\({}^{2}\) and 4 J/cm\({}^{2}\)) for three days, cell proliferation and nerve growth factor (NGF) gene expression were stimulated on day 20 [51]. However, emerging evidence also suggests a plausible role for blue light in neural stem cells (NSCs), the quiescent adult cells residing in specific regions of the mammalian brain;  
Figure 2: A schematic representation of putative protective effects on cell metabolism in the presence of PBM (**Panel B**) compared to those in the absence of PBM (**Panel A**). Abbreviation: transient receptor potential vanilloid 4 (TRPV4) cation channels. these, in fact, constitutively express blue and red light-sensitive photoreceptors. Indeed, [PERSON] et al. showed a 4.3-fold increase in proliferation and 2.7-fold increase in differentiation toward astrocyte phenotype of the abovementioned NSCs upon low-power blue monochromatic light exposure (455 nm, 300 \(\upmu\)W/cm\({}^{2}\)); the melanopsin (Opn4)/transient receptor potential channel 6 (TRPC6) non-visual opsin might serve as a key photoreceptor response to blue light irradiation. This also suggests that the blue light-triggered system of NSCs could enable nongenetic and non-invasive neuromodulation, with therapeutic potential for central nervous system diseases [55]. These findings are of relevance, as [PERSON] et al.