In vitro disease modeling of oculocutaneous albinism type 1 and 2 using human induced pluripotent stem cell-derived retinal pigment epithelium

Abstract

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.

Customized strategies for high-yield purification of retinal pigment epithelial cells differentiated from different stem cell sources

“…HDFa-RPE cells purified using various methods expressed PMEL17, a melanosome protein enriched in pigmented cells, and tight junction protein zonula occuldens-1 (ZO-1) (Fig. 4 a) 23 . Cytoplasmic expression of retinoid isomerohydrolase (RPE65) and Ezrin, a microvillus enriched protein, were also observed (Fig.…”

The Dct−/− Mouse Model to Unravel Retinogenesis Misregulation in Patients with Albinism

“…Melanosomes were identified and characterized (staging and shape) according to previously described criteria [ 24 , 25 , 26 , 27 ]. For quantification, melanosomes were scored on at least 4 independent areas of the tissue representing around 2 mm 2 of cytoplasmic surface for each genotype.…”

Spotlight on Three Rs Progress

“…The development of a stem cell-based model of oculocutaneous albinism (OCA), which encompasses autosomal recessive genetic conditions that affect pigmentation, has been reported in Stem Cells Reports . 1 OCA patients have genetic mutations that affect the production of melanin, leading to the absence of pigment in the eyes, skin and hair. In addition, they suffer from vision defects, namely reduced visual acuity, underdeveloped fovea and misrouted optic nerve fibres.…”

“…As there is limited availability of human cell lines for studying melanogenesis and pigmentation defects, 1 patient-derived iPSC lines can provide a consistent source of human tissue that is otherwise difficult to obtain. This human iPSC-based in vitro model for OCA could be useful for the study of the mechanisms underlying the defects seen in OCA, which remain poorly understood.…”

“…As there is no treatment for OCA, an easily available and human-relevant in vitro model might provide much needed tools to the field. The authors concluded that: “ In vitro derived OCA tissues and OCA-iRPE will allow deeper understanding of melanogenesis, enable the identification of molecules to rescue pigmentation defects, and further probe for molecular and/or physiologic differences.” 1…”