Stem cell reports · 2022
Cell-autonomous lipid-handling defects in Stargardt iPSC-derived retinal pigment epithelium cells.
СтатьяПоддержка NIH: внешняя программаResearch Support, N.I.H., IntramuralПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
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Farnoodian Mitra, Bose Devika, Khristov Vladimir, Susaimanickam Praveen Joseph, Maddileti Savitri, Mariappan Indumathi, Abu-Asab Mones, Campos Maria, Villasmil Rafael, Wan Qin, Maminishkis Arvydas, McGaughey David, Barone Francesca, Gundry Rebekah L, Riordon Daniel R, Boheler Kenneth R, Sharma Ruchi, Bharti Kapil
Аннотация
Stargardt retinopathy is an inherited form of macular degeneration caused by mutations in gene ABCA4 and characterized by the accumulation of lipid-rich deposits in the retinal pigment epithelium (RPE), RPE atrophy, and photoreceptor cell death. Inadequate mechanistic insights into pathophysiological changes occurring in Stargardt RPE have hindered disease treatments. Here, we show that ABCA4 knockout and induced pluripotent stem cell-derived RPE (STGD1-iRPE) from patients with Stargardt differentiate normally but display intracellular lipid and ceramide deposits reminiscent of the disease phenotype. STGD1-iRPE also shows defective photoreceptor outer segment (POS) processing and reduced cathepsin B activity-indicating higher lysosomal pH. Lipid deposits in STGD1-iRPE are lowered by increasing the activity of ABCA1, a lipid transporter, and ABCA4 ortholog. Our work suggests that ABCA4 is involved in POS and lipid handling in RPE cells and provides guidance for ongoing gene therapy approaches to target both RPE and photoreceptor cells for an effective treatment.