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Deregulation of neuro‐developmental genes and primary cilium cytoskeleton anomalies in iPSc‐derived retinal sheets from human syndromic ciliopathies

Modeling human developmental and degenerative diseases has been always logistically challenging in particular in the case of rare diseases where no exhaustive animal models are available. Generation of sustainable human disease models that allow in‐depth analysis of the molecular mechanism is one of the big challenges nowadays. Stem cell technology holds great potential in disease modeling and represents a new powerful tool for generating scalable and animal‐free models that can more accurately illustrate clinical phenotypes of complex human diseases. Ciliopathies are a group of heterogeneous genetic diseases affecting proteins involved in primary cilium structure and function. Syndromic ciliopathies have a broad spectrum of symptoms ranging from retinal degeneration to skeletal and neuro‐development anomalies, including polydactylism and mental retardation. Herein we describe the generation and molecular characterization of iPSC‐derived photoreceptor sheets from patients affected by ciliopathies. Photoreceptor sheets are characterized by a polarized, multi‐layered tissue expressing outer segment, connecting cilium, and nuclear photoreceptor markers. Ciliopathic photoreceptors displayed significant common alterations in the expression of hundreds of developmental genes. Moreover, they showed several anomalies in the formation and maintenance of cilia, the positioning of the mother centriole and the activation of a stress response to misfolded proteins. Furthermore, we observed genomic instabilities and accumulation of DNA damage in the photoreceptors progenitors of one of the patients. This study reveals how combining cell reprogramming and organogenesis technologies with nextgeneration sequencing enable the elucidation of molecular and cellular mechanisms involved in human ciliopathies. The same approach, combining photoreceptor sheet differentiation and wide genome expression profile could be applied to model many genetic, developmental and degenerative diseases affecting photoreceptors. These patient‐derived retinal sheets may be useful for elucidating the molecular mechanisms underlining these diseases, for drug screening of compounds with potential therapeutic effect and predicting drugs side effects.