Olivia Moharer

Age-related macular degeneration (AMD) is the leading cause of blindness in elderly people¹. The macula is the area of central vision and contains the retinal pigment epithelium (RPE) layer whose key function is phagocytosis of the photoreceptor outer segment (POS). Advancing age and genetic mutations in MerTK predispose individuals to developing AMD by decreasing phagocytosis resulting in a buildup of lipofuscin and drusen that thins and destroys the RPE via oxidative stress, free radial damage, and inflammation causing vision loss and retinal atrophy. AMD has two presentations, Wet and Dry. Anti–VEGF drugs effectively treat Wet AMD; however, no successful treatment exists for Dry AMD². Animal studies using MerTK knockout mice (-/-) have shown promise through injections of Human Umbilical Tissue Cells (hUTC) into RPE. hUTC secrete receptor tyrosine kinase (RTK) ligands and bridge molecules (BM) that bind to receptors in RPE and activate downstream signaling pathways shared by MerTK; therefore, hUTC secretions serve to offset the decrease or loss of MerTK function¹. RTK ligands such as BDNF, HGF, and GDNF augment phagocytosis in RPE. BM aid in opsonization and phagocytosis of the POS and include MFG-E8, Gas 6, TSP-1, and TSP-2. Cao et al. established that RTK ligands and BM increased phagocytic function of RPE in a dose dependent manner³. Koh et al. demonstrated that TSP-1 and TSP-2 advance excitatory connections in damaged RPE and stimulate stronger synaptic events⁴. Sun et al. focused on hUTC secreted PEDF⁵. PEDF is neuroprotective against RPE death induced by high levels of glutamate, ischemic injury, and hydrogen peroxide; therefore, PEDF may provide benefits to protect against the oxidative stress produced by lipofuscin and drusen accumulation.  Altogether, hUTC appears to positively impact the state of dysfunctional RPE through the secretion of RTK ligands, BM, and PEDF. By increasing RPE phagocytosis, hUTC may help to promote RPE survival, delay photoreceptor loss, and improve clinical symptoms of AMD; however, when applied in a clinical trial, the anticipated clinical results were not seen⁶. One year after an RPE transplant containing hUTC, the patient had no improvement in their visual acuity. Despite the evidence of rescued phagocytic function in the mouse model, human application trials have not fully provided the desired therapeutic effect; therefore, continued research, improved surgical implantation techniques, and greater sample sizes are needed to more effectively test the hypothesis that RTK ligands, BM, and PEDF from hUTC may ameliorate clinical symptoms of AMD.

References

1. Inana, G., Murat, C., An, W., Yao, X., Harris, I. R., & Cao, J. (2018). RPE phagocytic function declines in age-related macular degeneration and is rescued by human umbilical tissue derived cells. Journal of Translational Medicine,16(63). doi:https://doi.org/10.1186/s12967-018-1434-6
2. Nazari, H., Zhang, L., Zhu, D., Chader, G., Falabella, P., Stefanini, F., . . . Humayun, M. S. (2015). Stem cell based therapies for age-related macular degeneration: The promises and the challenges. Profess in Retinal and Eye Research,48, 1-39. http://dx.doi.org/10.1016/j.preteyeres.2015.06.004
3. Cao, J., Murat, C., An, W., Yao, X., Lee, J., Santulli-Marotto, S., . . . Inana, G. (2016). Human Umbilical Tissue-Derived Cells Rescue Retinal Pigment Epithelium Dysfunction in Retinal Degeneration. Stem Cells,34, 367-379. http://dx.doi.org/ 10.1002/stem.2239
4. Koh S, Kim N, Yin HH, Harris IR, Dejneka NS, Eroglu C. Human Umbilical Tissue-Derived Cells Promote Synapse Formation and Neurite Outgrowth Via Thrombospondin Family Proteins. The Journal of Neuroscience. 2015;35(47):15649-15665.
5. Sun J, Mandai M, Kamao H, et al. Protective Effects of Human iPS-Derived Retinal Pigmented Epithelial Cells in Comparison with Human Mesenchymal Stromal Cells and Human Neural Stem Cells on the Degenerating Retina inrd1mice. Stem Cells. 2015;33(5):1543-1553. doi:10.1002/stem.1960.
6. Mandai M, Watanabe A, Kurimoto Y, et al. Autologous Induced Stem-Cell–Derived Retinal Cells for Macular Degeneration. New England Journal of Medicine. 2017;377(8):792-793. doi:10.1056/nejmc1706274.