Primary Cilium-Mediated Retinal Pigment Epithelium Maturation Is Disrupted in Ciliopathy Patient Cells.
Primary Cilium-Mediated Retinal Pigment Epithelium Maturation Is Disrupted in Ciliopathy Patient Cells.
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DOI：
10.1016/j.celrep.2017.12.038
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发表时间：
2018-01-02
期刊：
影响因子：
8.8
通讯作者：
Bharti K
中科院分区：
文献类型：
--
作者：
May-Simera HL;Wan Q;Jha BS;Hartford J;Khristov V;Dejene R;Chang J;Patnaik S;Lu Q;Banerjee P;Silver J;Insinna-Kettenhofen C;Patel D;Lotfi M;Malicdan M;Hotaling N;Maminishkis A;Sridharan R;Brooks B;Miyagishima K;Gunay-Aygun M;Pal R;Westlake C;Miller S;Sharma R;Bharti K
初级纤毛是从细胞膜上伸出的感觉细胞器。原发纤毛的缺陷导致纤毛疾病，视网膜变性是突出的表型。在这里，我们证明了视网膜色素上皮(RPE)是光感受器发育和功能所必需的，需要一个功能正常的初级纤毛才能完全成熟，而纤毛疾病中的RPE成熟缺陷先于光感受器退化。在野生型诱导的多能干细胞(IPSC)-RPE中，药物增强的纤毛生成导致完全成熟和有功能的细胞。相比之下，纤毛运输蛋白缺失的患者来源的IPSC-RPE和IPSC-RPE仍然不成熟，顶突有缺陷，功能降低，成人特有的基因表达减少。初级纤毛的蛋白质通过同时抑制典型的WNT和激活PKCδ通路来调节视网膜色素上皮细胞的成熟。在肺上皮细胞中也存在类似的纤毛依赖成熟途径。我们的研究结果为研究纤毛病变引起的视网膜变性提供了深入的认识，证实了初级纤毛在上皮成熟中的发育作用，并为临床应用提供了一种成熟的IPSC上皮细胞的方法。May-Simera等人。结果表明，初级纤毛通过规范的WNT抑制和蛋白激酶Cδ激活来调节人IPSC-RPE、小鼠RPE和人IPSC-肺上皮的成熟和极化。睫状肌病变患者的RPE细胞存在结构和功能缺陷。这些结果为研究睫毛病变引起的视网膜变性提供了洞察力。
Primary cilia are sensory organelles that protrude from the cell membrane. Defects in the primary cilium cause ciliopathy disorders, with retinal degeneration as a prominent phenotype. Here, we demonstrate that the retinal pigment epithelium (RPE), essential for photoreceptor development and function, requires a functional primary cilium for complete maturation and that RPE maturation defects in ciliopathies precede photoreceptor degeneration. Pharmacologically enhanced ciliogenesis in wild-type induced pluripotent stem cells (iPSC)-RPE leads to fully mature and functional cells. In contrast, ciliopathy patient-derived iPSC-RPE and iPSC-RPE with a knockdown of ciliary-trafficking protein remain immature, with defective apical processes, reduced functionality, and reduced adult-specific gene expression. Proteins of the primary cilium regulate RPE maturation by simultaneously suppressing canonical WNT and activating PKCδ pathways. A similar cilium-dependent maturation pathway exists in lung epithelium. Our results provide insights into ciliopathy-induced retinal degeneration, demonstrate a developmental role for primary cilia in epithelial maturation, and provide a method to mature iPSC epithelial cells for clinical applications. May-Simera et al. show that primary cilia regulate the maturation and polarization of human iPSC-RPE, mouse RPE, and human iPSC-lung epithelium through canonical WNT suppression and PKCδ activation. RPE cells derived from ciliopathy patients exhibit defective structure and function. These results provide insights into ciliopathy-induced retinal degeneration.
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影响因子：
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通讯作者：
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