In vitro disease modeling of oculocutaneous albinism type 1 and 2 using human induced pluripotent stem cell-derived retinal pigment epithelium.
In vitro disease modeling of oculocutaneous albinism type 1 and 2 using human induced pluripotent stem cell-derived retinal pigment epithelium.
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DOI：
10.1016/j.stemcr.2021.11.016
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发表时间：
2022-01-11
影响因子：
5.9
通讯作者：
Brooks BP
中科院分区：
文献类型：
--
作者：
George A;Sharma R;Pfister T;Abu-Asab M;Hotaling N;Bose D;DeYoung C;Chang J;Adams DR;Cogliati T;Bharti K;Brooks BP
眼皮肤白化病(OCA)包括一组常染色体隐性遗传疾病，影响眼睛、皮肤和头发的色素沉着。OCA患者表现为最佳矫正视力降低，眼球色素沉着消失，中心凹发育异常，和/或视神经纤维异常交叉。据推测，改善眼睛色素沉着可以预防或挽救一些视力缺陷。本研究的目的是建立一种研究人视网膜色素上皮(RPE)色素缺陷的体外模型。我们为OCA1A型和OCA2型开发了一种“培养皿中的疾病”模型，使用诱导的多能干细胞来产生RPE。RPE是位于神经视网膜和脉络膜之间的单层细胞，呈多角形，着色、极化，在视觉中起着重要作用。在这里，我们显示了从OCA患者体外获得的RPE组织重现了白化病中所见的色素沉着缺陷，同时保留了组成RPE细胞的顶端-基底极性和正常的多边形形态。我们建立了一个基于IPSC的人眼皮肤白化(OCA)的体外模型。从OCA-IPSC衍生的iRPE保留了眼皮肤白化的顶端-基底的极性和多边形形态。OCA-iRPE重现了在白化病中看到的色素缺陷，过量的前黑素体和稀少的成熟黑素小体在OCA-iRPE中被发现。两个OCA-iRPE单层在形态上都是正常的，尽管细胞表型不同。色素沉着和黑素小体含量异常。OCA-iRPE模型将有助于解剖白化病视觉系统发育异常的潜在途径，并设计新的治疗方法。
Oculocutaneous albinism (OCA) encompasses a set of autosomal recessive genetic conditions that affect pigmentation in the eye, skin, and hair. OCA patients display reduced best-corrected visual acuity, reduced to absent ocular pigmentation, abnormalities in fovea development, and/or abnormal decussation of optic nerve fibers. It has been hypothesized that improving eye pigmentation could prevent or rescue some of the vision defects. The goal of the present study was to develop an in vitro model for studying pigmentation defects in human retinal pigment epithelium (RPE). We developed a “disease in a dish” model for OCA1A and OCA2 types using induced pluripotent stem cells to generate RPE. The RPE is a monolayer of cells that are pigmented, polarized, and polygonal in shape, located between the neural retina and choroid, with an important role in vision. Here we show that RPE tissue derived in vitro from OCA patients recapitulates the pigmentation defects seen in albinism, while retaining the apical-basal polarity and normal polygonal morphology of the constituent RPE cells. We established a human iPSC-based in vitro model for oculocutaneous albinism (OCA) iRPE derived from OCA-iPSC retains apical-basal polarity and polygonal morphology OCA-iRPE recapitulates the pigmentation defect seen in albinism Excess pre-melanosomes and scarce mature melanosomes are found in OCA-iRPE In this article, Brooks and colleagues establish an iPSC-derived retinal pigment epithelium (iRPE) model of two forms of oculocutaneous albinism, OCA1A and OCA2. Both OCA-iRPE monolayers are morphologically normal, albeit with differences in cellular phenotypes. Pigmentation and melanosome content are abnormal. OCA-iRPE models will help with dissecting the pathways underlying abnormalities in visual system development in albinism and devising novel treatments.
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