Novel Human Induced Pluripotent Stem Cell-Based Model for Retinal Pigment Epithelial Cells to Reveal Possible Disease Mechanisms for Macular Degeneration in Pseudoxanthoma Elasticum.

IF 1.8 4区 医学 Q3 OPHTHALMOLOGY
Journal of Ophthalmology Pub Date : 2024-09-21 eCollection Date: 2024-01-01 DOI:10.1155/2024/6939920
Taina Viheriälä, Heidi Hongisto, Lyydia Saari, Marika Oksanen, Tanja Ilmarinen, Suvi Väärämäki, Hannu Uusitalo, Pasi Nevalainen, Heli Skottman
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Abstract

Pseudoxanthoma elasticum (PXE) is a rare metabolic disease with autosomal recessive inheritance. The manifestation in PXE is represented by retinal complications, pseudoxanthomas of the skin folding areas, and arterial calcification. The retinal complications are caused by the calcification of Bruch's membrane beneath retinal pigment epithelial cells (RPE) that can lead to retinal macular degeneration. The exact mechanism for the retinal pathophysiology is not known, and patients have variable symptoms and findings. Two induced pluripotent stem cell (hiPSC) lines from a patient carrying the common homozygous mutation c.3421C > T, p.Arg1141X in the ATP-binding cassette transporter gene (ABCC6; OMIM264800) were established and fully characterized. Then, RPE cells were differentiated, and molecular and functional characterization was conducted as a comparison to healthy controls. Data demonstrated that PXE-specific high-quality hiPSC lines can be established from a skin biopsy regardless of the skin-related disease phenotype and disease-specific RPE differentiation is feasible. The molecular and functional assessment of the PXE-specific RPE indicated increased pigmentation and reduced epithelial barrier functions as well as phagocytosis activity as compared to healthy controls. Although preliminary data, this indicates possible RPE-dependent factors that might explain the individual vulnerability of the retinas for macular degeneration in PXE. Future validation of the novel findings with additional PXE patients will be important.

基于新型人类诱导多能干细胞的视网膜色素上皮细胞模型,揭示假黄疽弹性体黄斑变性的可能疾病机理。
假黄疽(PXE)是一种罕见的常染色体隐性遗传代谢病。PXE 的表现形式包括视网膜并发症、皮肤褶皱部位的假黄瘤和动脉钙化。视网膜并发症是由视网膜色素上皮细胞(RPE)下方的布鲁氏膜钙化引起的,可导致视网膜黄斑变性。视网膜病理生理学的确切机制尚不清楚,患者的症状和检查结果也各不相同。我们从一名携带 ATP 结合盒转运体基因(ABCC6;OMIM264800)c.3421C > T, p.Arg1141X 常见同源突变的患者身上建立了两个诱导多能干细胞(hiPSC)系,并对其进行了全面鉴定。然后,对 RPE 细胞进行分化,并与健康对照组进行分子和功能特性比较。数据表明,无论皮肤相关疾病的表型如何,都可以通过皮肤活检建立 PXE 特异性高质量 hiPSC 株系,而且疾病特异性 RPE 分化是可行的。与健康对照组相比,PXE 特异性 RPE 的分子和功能评估显示色素沉着增加、上皮屏障功能和吞噬活性降低。虽然是初步数据,但这表明可能存在依赖于 RPE 的因素,这些因素可能解释了 PXE 患者视网膜黄斑变性的个体脆弱性。未来在更多的 PXE 患者身上验证这些新发现将非常重要。
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来源期刊
Journal of Ophthalmology
Journal of Ophthalmology MEDICINE, RESEARCH & EXPERIMENTAL-OPHTHALMOLOGY
CiteScore
4.30
自引率
5.30%
发文量
194
审稿时长
6-12 weeks
期刊介绍: Journal of Ophthalmology is a peer-reviewed, Open Access journal that publishes original research articles, review articles, and clinical studies related to the anatomy, physiology and diseases of the eye. Submissions should focus on new diagnostic and surgical techniques, instrument and therapy updates, as well as clinical trials and research findings.
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