Loss of photoreceptors is a common endpoint in degenerative retinal diseases. Human pluripotent stem cells provide a potential source for photoreceptor replacement, but, even in mouse models, the efficiency and efficacy of transplantation-based repair remains poor. In this study, we examined the degree to which immune rejection contributes to these disappointing outcomes using an immunodeficient IL2 receptor γ (IL2rγ)-null mouse model. Our results show that prevention of cell rejection in the normal and degenerating retinal environment significantly improves long-term survival and integration of hESC-derived donor retinal cells. Transplanted cells are able to differentiate into mature photoreceptors expressing various opsins and can functionally integrate into congenitally blind mice. Our work suggests that even though the retina is often considered immune-privileged, suppression of host immune-mediated cell rejection may well be a useful approach for improving long-term integration of transplanted cells with a view to successful clinical outcomes.

Retinal degeneration often results in the loss of light‐sensing photoreceptors, which leads to permanent vision loss. Generating transplantable retinal photoreceptors using human somatic cell‐derived induced pluripotent stem cells (iPSCs) holds promise to treat a variety of retinal degenerative diseases by replacing the damaged or dysfunctional native photoreceptors with healthy and functional ones. Establishment of effective methods to produce retinal cells including photoreceptors in chemically defined conditions using current Good Manufacturing Practice (cGMP)‐manufactured human iPSC lines is critical for advancing cell replacement therapy to the clinic. In this study, we used a human iPSC line (NCL‐1) derived under cGMP‐compliant conditions from CD34+ cord blood cells. The cells were differentiated into retinal cells using a small molecule‐based retinal induction protocol. We show that retinal cells including photoreceptors, retinal pigmented epithelial cells and optic cup‐like retinal organoids can be generated from the NCL‐1 iPSC line. Additionally, we show that following subretinal transplantation into immunodeficient host mouse eyes, retinal cells successfully integrated into the photoreceptor layer and developed into mature photoreceptors. This study provides strong evidence that transplantable photoreceptors can be generated from a cGMP‐manufactured human iPSC line for clinical applications. Stem Cells Translational Medicine 2018;7:210–219

Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer's disease (AD) and related tauopathies. Here, we define a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIdney/BRAin (KIBRA) protein (CT-KIBRA). We show that CT-KIBRA restores plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we find that CT-KIBRA binds to and stabilizes protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau-mediated pathogenesis. In humans we find that reduced KIBRA in brain and increased KIBRA in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. Thus, our results distinguish KIBRA both as a novel biomarker of synapse dysfunction in AD and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.

Age-related macular degeneration (AMD) is one of several retinal degenerative diseases that results in a person's loss of vision due to retinal damage (1). The retina contains two types of photoreceptors called rods and cones. Rod photoreceptors are light sensitive and abundant in the retina.

Many neurodegenerative diseases are characterized by accumulation of proteins such as tau, a microtubule stabilization protein. Toxic tau forms tangles and affects neuronal synapse function, an early step of neurodegeneration. To focus on synapse function, we highlighted Caprin-1 protein. Through gene ontology, Caprin-1 is related to RNA granule proteins, important for transport and local translation in dendrites. Caprin-1 is of interest for neurodegeneration because it is a memory related protein, transports mRNA in RNA granules, and knock out mice demonstrate memory deficits. As we age, the performance of local translation in the dendrites is compromised and leads to synapse dysfunction. We hypothesize Caprin-1 binds to Tau and becomes disrupted. This leads to the dissolution of RNA granules, inhibition of mRNA transport in dendrites, suppression of translation, and failure of synapse. Early western blot data showed reduced Caprin-1 in PS19 Tau+, supporting our model that Caprin-1 is disrupted in disease models. Through immunohistochemistry, we investigated the localization of Caprin-1 in the mouse hippocampus. We observed Caprin-1 localization to dendrites of CA1 neurons in the hippocampus. Furthermore, Caprin-1 exhibited colocalization with Rps6, an RNA granule marker. This suggests Caprin-1 associates with RNA granules in mouse hippocampus. Finally, we investigated the localization of Caprin-1 in human iPSC-derived neurons. Similar to the mouse hippocampus, we observed localization of Caprin-1 to dendrites of human neurons. In future directions, we will examine whether pathogenic tau alters the association of Caprin-1 with RNA granules and the mechanisms by which pathogenic tau negatively effects synapse function.