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Open AccessArticle

Aberrant hiPSCs-Derived from Human Keratinocytes Differentiates into 3D Retinal Organoids that Acquire Mature Photoreceptors

1
Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan
2
Institute of Eye Research, Hualien Tzu Chi General Hospital, Hualien 970, Taiwan
3
Department of Obstetrics and Gynecology, Hualien Tzu Chi General Hospital, Hualien 970, Taiwan
*
Author to whom correspondence should be addressed.
Cells 2019, 8(1), 36; https://doi.org/10.3390/cells8010036
Received: 30 September 2018 / Revised: 12 December 2018 / Accepted: 3 January 2019 / Published: 9 January 2019
(This article belongs to the Special Issue Stem Cells in Personalized Medicine)
Human induced pluripotent stem cell (hiPSC)-derived three-dimensional retinal organoids are a new platform for studying the organoidogenesis. However, recurrent genomic aberration, acquired during generation of hiPSCs, limit its biomedical application and/or aberrant hiPSCs has not been evaluated for generation of differentiated derivatives, such as organoids and retinal pigment epithelium (RPE). In this study, we efficiently differentiated mosaic hiPSCs into retinal organoids containing mature photoreceptors. The feeder-free hiPSCs were generated from the human epidermal keratinocytes that were rapid in process with improved efficiency over several passages and maintained pluripotency. But, hiPSCs were cytogenetically mosaic with normal and abnormal karyotypes, while copy number variation analysis revealed the loss of chromosome 8q. Despite this abnormality, the stepwise differentiation of hiPSCs to form retinal organoids was autonomous and led to neuronal lamination. Furthermore, the use of a Notch inhibitor, DAPT, at an early timepoint from days 29–42 of culture improved the specification of the retinal neuron and the use of retinoic acid at days 70–120 led to the maturation of photoreceptors. hiPSC-derived retinal organoids acquired all subtypes of photoreceptors, such as RHODOPSIN, B-OPSIN and R/G-OPSIN. Additionally, the advanced maturation of photoreceptors was observed, revealing the development of specific sensory cilia and the formation of the outer-segment disc. This report is the first to show that hiPSCs with abnormal chromosomal content are permissive to the generation of three-dimensional retinal organoids. View Full-Text
Keywords: keratinocytes; hiPSCs; genomic aberrations; retinal organoids; photoreceptors keratinocytes; hiPSCs; genomic aberrations; retinal organoids; photoreceptors
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MDPI and ACS Style

Shrestha, R.; Wen, Y.-T.; Ding, D.-C.; Tsai, R.-K. Aberrant hiPSCs-Derived from Human Keratinocytes Differentiates into 3D Retinal Organoids that Acquire Mature Photoreceptors. Cells 2019, 8, 36.

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