Aberrant Retinal Pigment Epithelial Cells Derived from Induced Pluripotent Stem Cells of a Retinitis Pigmentosa Patient with the PRPF6 Mutation

Abstract

Pre-mRNA processing factors (PRPFs) are vital components of the spliceosome and are involved in the physiological process necessary for pre-mRNA splicing to mature mRNA. As an important member, PRPF6 mutation resulting in autosomal dominant retinitis pigmentosa (adRP) is not common. Recently, we reported the establishment of an induced pluripotent stem cells (iPSCs; CSUASOi004-A) model by reprogramming the peripheral blood mononuclear cells of a PRPF6-related adRP patient, which could recapitulate a consistent disease-specific genotype. In this study, a disease model of retinal pigment epithelial (RPE) cells was generated from the iPSCs of this patient to further investigate the underlying molecular and pathological mechanisms. The results showed the irregular morphology, disorganized apical microvilli and reduced expressions of RPE-specific genes in the patient’s iPSC-derived RPE cells. In addition, RPE cells carrying the PRPF6 mutation displayed a decrease in the phagocytosis of fluorescein isothiocyanate-labeled photoreceptor outer segments and exhibited impaired cell polarity and barrier function. This study will benefit the understanding of PRPF6-related RPE cells and future cell therapy.

Application of patient-derived induced pluripotent stem cells and organoids in inherited retinal diseases

“…In addition, ROs and RPE models from patient-specific iPSCs with the PRPF31 mutation showed impaired pre-mRNA splicing process as described by Baskin et al On the other hand, abnormal photoreceptor and RPE changes were also observed, including cell morphology, cilium structure, apical-basal polarity, and phagocytosis function of the photoreceptor outer segment (POS) [ 41 ]. Such an aberrant phenotype was also observed in iPSC-RPE cells from the PRPF6- mutated patients [ 42 ]. These reports suggested that progressive RPE and photoreceptor degeneration might be attributed to the mis-splicing of genes vital for retinal structure and function.…”

Features of generation and differentiation of induced pluripotent stem cells into retinal cells for modeling human hereditary diseases

“…Клетки сетчатки, полученные из ИПСК пациента с макулярной телеангиэктазией, демонстрировали нарушение митохондриальной функции [46]. Аномальные клетки пигментного эпителия образовывались из ИПСК пациента с пигментным ретинитом [47]. А в другом исследовании моделирование пигментного ретинита с помощью полученных из ИПСК ретиноидных органоидов показало массированную гибель клеток после их формирования [48].…”