Background Age-related macular degeneration (AMD) is a result of degeneration/damage of the retinal pigment epithelium (RPE) while retinitis pigmentosa (RP), an inherited early-onset disease, results from premature loss of photoreceptors. A promising therapeutic approach for both is the replacement of lost/damaged cells with human induced pluripotent stem cell (hiPSC)-derived retinal cells. Methods The aim of this study was to investigate the in vivo functionality of RPE and photoreceptor progenitor (PRP) cells derived from a clinical-grade hiPSC line through a unified protocol. De novo-generated RPE and PRP were characterized extensively to validate their identity, purity, and potency. Results RPE expressed tight junction proteins, showed pigmentation and ciliation, and secreted polarization-related factors vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF). PRP expressed neural retina proteins and cone and rod markers, and responded to KCl-induced polarization. Transcriptomic analysis demonstrated an increase in the expression of mature retinal tissue-specific genes coupled with concomitant downregulation of genes from undesired lineages. RPE transplantation rescued visual function in RCS rats shown via optokinetic tracking and photoreceptor rescue. PRP transplantation improved light perception in NOD.SCID-rd1 mice, and positive electroretinography signals indicated functional photoreceptor activity in the host’s outer nuclear layer. Graft survival and integration were confirmed using immunohistochemistry, and no animals showed teratoma formation or any kind of ectopic growth in the eye. Conclusions To our knowledge, this is the first demonstration of a unified, scalable, and GMP-adaptable protocol indicating strong animal efficacy and safety data with hiPSC-derived RPE and PRP cells. These findings provide robust proof-of-principle results for IND-enabling studies to test these potential regenerative cell therapies in patients.

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The lung is the most vulnerable target for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, and respiratory failure causing acute respiratory distress syndrome is its foremost outcome. However, the current primary in vitro models in use for SARS-CoV-2 display apparent limitations for modeling such complex human respiratory disease. Although patient cells can directly model the effects of a drug, their availability and capacity for expansion are limited compared with transformed/immortalized cells or tumor-derived cell lines. An additional caveat is that the latter may harbor genetic and metabolic abnormalities making them unsuitable for drug screening. Therefore, it is important to create physiologically relevant human-cell models that can replicate the pathophysiology of SARS-CoV-2, thus facilitating drug testing. In this study, we show preliminary data on how human induced pluripotent stem cells-derived lung epithelial cell system could emerge as a relevant and sensitive platform for modeling SARS-CoV-2 infection and drug screening.

Increased cellular concentration of α-synuclein (α-syn) predisposes it to misfolding and aggregation that in turn impair the degradation pathways. This poses a limitation to the use of overexpression models for studies on α-syn clearance by autophagy, which is widely investigated for its therapeutic potential. This limitation can be overcome with the use of endogenous models. In this study, SK-MEL-28, a melanoma cell model with endogenous α-syn expression, was employed to study α-syn clearance through autophagy. We demonstrated the dual localization of α-syn to nucleus and cytoplasm that varied in response to changes in cellular environment. Autophagy inhibition and exposure to dopamine favored cytoplasmic localization of α-syn, while autophagy induction favored increased localization to the nucleus. The inhibitory effect of dopamine on autophagy was heightened in presence of α-syn. Additionally, because α-syn had a regulatory effect on autophagy, cells showed an increased resistance to autophagy induction in presence of α-syn. This resistance prevented effective induction of autophagy even under conditions of prolonged autophagy inhibition. These results highlight alternate physiological roles of α-syn, particularly in non-neuronal cells. Because autophagy enhancement could reverse neither the increase in α-syn levels nor the autophagy inhibition, there arises a need to evaluate the efficacy of autophagy-based therapeutic strategies.