HUMAN CELLULAR MODELS FOR RETINAL DISEASE: From Induced Pluripotent Stem Cells to Organoids.

PURPOSE: To provide a concise review of induced pluripotent stem cells (iPSCs) and retinal organoids as models for human retinal diseases and their role in gene discovery and treatment of inherited retinal diseases (IRDs). METHODS: A PubMed literature review was performed for models of human retinal disease, including animal models and human pluripotent stem cell-derived models. RESULTS: There is a growing body of research on retinal disease using human pluripotent stem cells. This is a significant change from just a decade ago when most research was performed on animal models. The advent of induced pluripotent stem cells has permitted not only the generation of two-dimensional human cell cultures such as RPE but also more recently the generation of three-dimensional retinal organoids that better reflect the multicellular laminar architecture of the human retina. CONCLUSION: Modern stem cell techniques are improving our ability to model human retinal disease in vitro, especially with the use of patient-derived induced pluripotent stem cells. In the future, a personalized approach may be used in which the individual's unique genotype can be modeled in two-dimensional culture or three-dimensional organoids and then rescued with an optimized therapy before treating the patient.

GIV/Girdin promotes cell survival during endoplasmic reticulum stress.

Endoplasmic reticulum (ER) stress is a form of cellular stress that is experienced by cells both under normal physiological conditions such as in professional secretory cells and disease states such as cancer, diabetes, and neurodegeneration. Upon facing ER stress, cells activate a conserved signaling pathway called the unfolded protein response (UPR) to restore normal function by halting general protein translation, upregulating expression of chaperones, and promoting ER-associated degradation. However, if the stress is overwhelming and cells are not able to recover within a reasonable time frame, the UPR ultimately commits cells to programmed cell death. How cells make this life-or-death decision remains an exciting yet poorly understood phenomenon. Here, we show that Gα-interacting vesicle-associated protein (GIV) aka Girdin plays an important role in promoting cell survival during ER stress. Cells lacking GIV are impaired in activating the pro-survival Akt pathway upon induction of ER stress. These cells also show enhanced levels of the pro-apoptotic transcription factor, CCAAT/enhancer binding protein homologous protein (CHOP) as compared to control cells. Due to decreased pro-survival signals and a concomitant increase in pro-apoptotic signals, GIV-depleted cells show a significant reduction in cell survival upon prolonged ER stress which can be rescued by re-expression of GIV or by directly activating Akt in these cells. Together, this study shows a novel, cytoprotective role for GIV in ER-stressed cells and furthers our understanding of the mechanisms that contribute to cell survival during ER stress.