Hum Mol Genet：iPS可以作为遗传性黄斑变性的新型干细胞模型

近日，来自美国威斯康星大学的研究者使用诱导多能干细胞技术（iPS）将病人的皮肤组织成功转变成了遗传性黄斑变性的实验室模型。相关研究成果刊登于国际杂志Human Molecular Genetics上。

研究者Gamm表示，这种模型可以帮助我们更加快速深入地理解人类基因突变的生物学效应。我们希望这种新型模型可以帮助我们开发出新型疗法用以减缓或者逆转贝斯特病。贝斯特病是一种罕见的、病人特异性模型的眼疾，其可以破坏视网膜的斑点，引发黄斑变性。

这种新型模型揭示了一些促使疾病发生的细胞反应过程，贝斯特病病人的模型展示了一种液体以及古老的视网膜感光细胞的组织结构，揭示了一种降解并移去死细胞能力的错误或缺失。从分子水平来讲，贝斯特细胞降解视网膜紫质的速度很慢，而视网膜紫质是一种感光细胞的生物色素，其在钙信号和氧化性应激方面存在明显差异。

本文的研究结果为研究者寻找新型疾病的疗法带来了帮助，而且这个干细胞模型可以帮助研究者检测新型疗法的效果。更为重要的是，这项研究发现为治疗家族性人群的疾病提供了巨大帮助，这将帮助他们理解疾病的发病过程以及分子机制。

研究者最后说，对这项创新性研究我们表示非常高兴，利用新型的干细胞模型可以更好地理解复杂的视网膜疾病，这就离开发新型疗法更近了一步，而且研究成果可以帮助我们克服一系列遗传性的视网膜疾病。

编译自：Cells from Skin Create Model of Blinding Eye Disease

doi:10.1093/hmg/dds469
PMC:
PMID:

iPS cell modeling of Best disease: Insights into the pathophysiology of an inherited macular degeneration

Ruchira Singh1,*, Wei Shen1,*, David Kuai1, Jessica M. Martin1, Xiangrong Guo1, Molly A. Smith1, Enio T. Perez1, Michael J. Phillips1, Joseph M. Simonett1, Kyle A. Wallace1, Amelia D. Verhoeven1, Elizabeth E. Capowski1, Xiaoqing Zhang1, Yingnan Yin1, Patrick J. Halbach3, Gerald A. Fishman2, Lynda S. Wright1, Bikash R. Pattnaik3,5 and David M. Gamm1,3,4,5,#

Best disease (BD) is an inherited degenerative disease of the human macula that results in progressive and irreversible central vision loss. It is caused by mutations in the retinal pigment epithelium (RPE) gene BESTROPHIN1 (BEST1), which, through mechanism(s) that remain unclear, lead to the accumulation of subretinal fluid and autofluorescent waste products from shed photoreceptor outer segments (POS). We employed human iPS cell (hiPSC) technology to generate RPE from BD patients and unaffected siblings in order to examine the cellular and molecular processes underlying this disease. Consistent with the clinical phenotype of BD, RPE from mutant hiPSCs displayed disrupted fluid flux and increased accrual of autofluorescent material after long-term POS feeding when compared to hiPSC-RPE from unaffected siblings. On a molecular level, RHODOPSIN degradation after POS feeding was delayed in BD hiPSC-RPE relative to unaffected sibling hiPSC-RPE, directly implicating impaired POS handling in the pathophysiology of the disease. In addition, stimulated calcium responses differed between BD and normal sibling hiPSC-RPE, as did oxidative stress levels after chronic POS feeding. Subcellular localization, fractionation, and co-immunoprecipitation experiments in hiPSC-RPE and human prenatal RPE further linked BEST1 to the regulation and release of endoplasmic reticulum calcium stores. Since calcium signaling and oxidative stress are critical regulators of fluid flow and protein degradation, these findings likely contribute to the clinical picture of BD. In a larger context, this report demonstrates the potential to use patient-specific hiPSCs to model and study maculopathies, an important class of blinding disorders in humans.

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