ABSTRACT
Photoreceptor loss is a leading cause of blindness, but mechanisms underlying photoreceptor degeneration are not well understood. Treatment strategies would benefit from improved understanding of gene-expression patterns directing photoreceptor development, as many genes are implicated in both development and degeneration. Neural retina leucine zipper (NRL) is critical for rod photoreceptor genesis and degeneration, with NRL mutations known to cause enhanced S-cone syndrome and retinitis pigmentosa. While murine Nrl loss has been characterized, studies of human NRL can identify important insights for human retinal development and disease. We utilized iPSC organoid models of retinal development to molecularly define developmental alterations in a human model of NRL loss. Consistent with the function of NRL in rod fate specification, human retinal organoids lacking NRL develop S-opsin dominant photoreceptor populations. We report generation of two distinct S-opsin expressing populations in NRL null retinal organoids and identify MEF2C as a candidate regulator of cone development.
Subject(s)
Basic-Leucine Zipper Transcription Factors/genetics , Eye Proteins/genetics , Induced Pluripotent Stem Cells/physiology , Organoids/pathology , Retina/pathology , Retinal Cone Photoreceptor Cells/physiology , Basic-Leucine Zipper Transcription Factors/deficiency , Case-Control Studies , Cell Differentiation/genetics , Cells, Cultured , Cellular Reprogramming/physiology , Eye Diseases, Hereditary/genetics , Eye Diseases, Hereditary/pathology , Fetus/pathology , Gene Expression Profiling , Humans , Nerve Regeneration/genetics , Neurogenesis/genetics , Organoids/physiology , Primary Cell Culture/methods , Retina/physiology , Retinal Degeneration/genetics , Retinal Degeneration/pathology , Retinitis Pigmentosa/genetics , Retinitis Pigmentosa/pathology , Transcriptome , Vision Disorders/genetics , Vision Disorders/pathologyABSTRACT
As applications of human pluripotent stem cells (hPSCs) continue to be refined and pursued, it is important to keep in mind that the strengths and weaknesses of this technology lie with its developmental origins. The remarkable capacity of differentiating hPSCs to recapitulate cell and tissue genesis has provided a model system to study stages of human development that were not previously amenable to investigation and experimentation. Furthermore, demonstration of developmentally appropriate, stepwise differentiation of hPSCs to specific cell types offers support for their authenticity and their suitability for use in disease modeling and cell replacement therapies. However, limitations to farming cells and tissues in an artificial culture environment, as well as the length of time required for most cells to mature, are some of the many issues to consider before using hPSCs to study or treat a particular disease. Given the overarching need to understand and modulate the dynamics of lineage-specific differentiation in stem cell cultures, this review will first examine the capacity of hPSCs to serve as models of retinal development. Thereafter, we will discuss efforts to model retinal disorders with hPSCs and present challenges that face investigators who aspire to use such systems to study disease pathophysiology and/or screen for therapeutics. We also refer readers to recent publications that provide additional insight and details on these rapidly evolving topics.
