Morphological and Molecular Defects in Human Three-Dimensional Retinal Organoid Model of X-Linked Juvenile Retinoschisis

Kang Chieh Huang; Mong Lien Wang; Shih Jen Chen; Jean Cheng Kuo; Won Jing Wang; Phan Nguyen Nhi Nguyen; Karl J. Wahlin; Jyh Feng Lu; Audrey A. Tran; Michael Shi; Yueh Chien; Aliaksandr A. Yarmishyn; Ping Hsing Tsai; Tien Chun Yang; Wann Neng Jane; Chia-Ching Chang; Chi Hsien Peng; Thorsten M. Schlaeger; Shih Hwa Chiou

doi:10.1016/j.stemcr.2019.09.010

Morphological and Molecular Defects in Human Three-Dimensional Retinal Organoid Model of X-Linked Juvenile Retinoschisis

Kang Chieh Huang, Mong Lien Wang, Shih Jen Chen, Jean Cheng Kuo, Won Jing Wang, Phan Nguyen Nhi Nguyen, Karl J. Wahlin, Jyh Feng Lu, Audrey A. Tran, Michael Shi, Yueh Chien, Aliaksandr A. Yarmishyn, Ping Hsing Tsai, Tien Chun Yang, Wann Neng Jane, Chia-Ching Chang, Chi Hsien Peng, Thorsten M. Schlaeger^*, Shih Hwa Chiou

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

77 Scopus citations

Abstract

X-linked juvenile retinoschisis (XLRS), linked to mutations in the RS1 gene, is a degenerative retinopathy with a retinal splitting phenotype. We generated human induced pluripotent stem cells (hiPSCs) from patients to study XLRS in a 3D retinal organoid in vitro differentiation system. This model recapitulates key features of XLRS including retinal splitting, defective retinoschisin production, outer-segment defects, abnormal paxillin turnover, and impaired ER-Golgi transportation. RS1 mutation also affects the development of photoreceptor sensory cilia and results in altered expression of other retinopathy-associated genes. CRISPR/Cas9 correction of the disease-associated C625T mutation normalizes the splitting phenotype, outer-segment defects, paxillin dynamics, ciliary marker expression, and transcriptome profiles. Likewise, mutating RS1 in control hiPSCs produces the disease-associated phenotypes. Finally, we show that the C625T mutation can be repaired precisely and efficiently using a base-editing approach. Taken together, our data establish 3D organoids as a valid disease model.

Original language	English
Pages (from-to)	906-923
Number of pages	18
Journal	Stem Cell Reports
Volume	13
Issue number	5
DOIs	https://doi.org/10.1016/j.stemcr.2019.09.010
State	Published - 12 Nov 2019

Keywords

CRISPR/Cas9 gene editing
RS1
X-linked juvenile retinoschisis
induced pluripotent stem cells
retinal degeneration
retinal organoid
retinogenesis
retinoschisin

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Huang, K. C., Wang, M. L., Chen, S. J., Kuo, J. C., Wang, W. J., Nhi Nguyen, P. N., Wahlin, K. J., Lu, J. F., Tran, A. A., Shi, M., Chien, Y., Yarmishyn, A. A., Tsai, P. H., Yang, T. C., Jane, W. N., Chang, C.-C., Peng, C. H., Schlaeger, T. M., & Chiou, S. H. (2019). Morphological and Molecular Defects in Human Three-Dimensional Retinal Organoid Model of X-Linked Juvenile Retinoschisis. Stem Cell Reports, 13(5), 906-923. https://doi.org/10.1016/j.stemcr.2019.09.010

@article{85d217ee475649db90123c7cf37894eb,

title = "Morphological and Molecular Defects in Human Three-Dimensional Retinal Organoid Model of X-Linked Juvenile Retinoschisis",

abstract = " X-linked juvenile retinoschisis (XLRS), linked to mutations in the RS1 gene, is a degenerative retinopathy with a retinal splitting phenotype. We generated human induced pluripotent stem cells (hiPSCs) from patients to study XLRS in a 3D retinal organoid in vitro differentiation system. This model recapitulates key features of XLRS including retinal splitting, defective retinoschisin production, outer-segment defects, abnormal paxillin turnover, and impaired ER-Golgi transportation. RS1 mutation also affects the development of photoreceptor sensory cilia and results in altered expression of other retinopathy-associated genes. CRISPR/Cas9 correction of the disease-associated C625T mutation normalizes the splitting phenotype, outer-segment defects, paxillin dynamics, ciliary marker expression, and transcriptome profiles. Likewise, mutating RS1 in control hiPSCs produces the disease-associated phenotypes. Finally, we show that the C625T mutation can be repaired precisely and efficiently using a base-editing approach. Taken together, our data establish 3D organoids as a valid disease model.",

keywords = "CRISPR/Cas9 gene editing, RS1, X-linked juvenile retinoschisis, induced pluripotent stem cells, retinal degeneration, retinal organoid, retinogenesis, retinoschisin",

author = "Huang, {Kang Chieh} and Wang, {Mong Lien} and Chen, {Shih Jen} and Kuo, {Jean Cheng} and Wang, {Won Jing} and {Nhi Nguyen}, {Phan Nguyen} and Wahlin, {Karl J.} and Lu, {Jyh Feng} and Tran, {Audrey A.} and Michael Shi and Yueh Chien and Yarmishyn, {Aliaksandr A.} and Tsai, {Ping Hsing} and Yang, {Tien Chun} and Jane, {Wann Neng} and Chia-Ching Chang and Peng, {Chi Hsien} and Schlaeger, {Thorsten M.} and Chiou, {Shih Hwa}",

note = "Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = nov,

day = "12",

doi = "10.1016/j.stemcr.2019.09.010",

language = "English",

volume = "13",

pages = "906--923",

journal = "Stem Cell Reports",

issn = "2213-6711",

publisher = "Cell Press",

number = "5",

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Huang, KC, Wang, ML, Chen, SJ, Kuo, JC, Wang, WJ, Nhi Nguyen, PN, Wahlin, KJ, Lu, JF, Tran, AA, Shi, M, Chien, Y, Yarmishyn, AA, Tsai, PH, Yang, TC, Jane, WN, Chang, C-C, Peng, CH, Schlaeger, TM & Chiou, SH 2019, 'Morphological and Molecular Defects in Human Three-Dimensional Retinal Organoid Model of X-Linked Juvenile Retinoschisis', Stem Cell Reports, vol. 13, no. 5, pp. 906-923. https://doi.org/10.1016/j.stemcr.2019.09.010

TY - JOUR

T1 - Morphological and Molecular Defects in Human Three-Dimensional Retinal Organoid Model of X-Linked Juvenile Retinoschisis

AU - Huang, Kang Chieh

AU - Wang, Mong Lien

AU - Chen, Shih Jen

AU - Kuo, Jean Cheng

AU - Wang, Won Jing

AU - Nhi Nguyen, Phan Nguyen

AU - Wahlin, Karl J.

AU - Lu, Jyh Feng

AU - Tran, Audrey A.

AU - Shi, Michael

AU - Chien, Yueh

AU - Yarmishyn, Aliaksandr A.

AU - Tsai, Ping Hsing

AU - Yang, Tien Chun

AU - Jane, Wann Neng

AU - Chang, Chia-Ching

AU - Peng, Chi Hsien

AU - Schlaeger, Thorsten M.

AU - Chiou, Shih Hwa

PY - 2019/11/12

Y1 - 2019/11/12

N2 - X-linked juvenile retinoschisis (XLRS), linked to mutations in the RS1 gene, is a degenerative retinopathy with a retinal splitting phenotype. We generated human induced pluripotent stem cells (hiPSCs) from patients to study XLRS in a 3D retinal organoid in vitro differentiation system. This model recapitulates key features of XLRS including retinal splitting, defective retinoschisin production, outer-segment defects, abnormal paxillin turnover, and impaired ER-Golgi transportation. RS1 mutation also affects the development of photoreceptor sensory cilia and results in altered expression of other retinopathy-associated genes. CRISPR/Cas9 correction of the disease-associated C625T mutation normalizes the splitting phenotype, outer-segment defects, paxillin dynamics, ciliary marker expression, and transcriptome profiles. Likewise, mutating RS1 in control hiPSCs produces the disease-associated phenotypes. Finally, we show that the C625T mutation can be repaired precisely and efficiently using a base-editing approach. Taken together, our data establish 3D organoids as a valid disease model.

AB - X-linked juvenile retinoschisis (XLRS), linked to mutations in the RS1 gene, is a degenerative retinopathy with a retinal splitting phenotype. We generated human induced pluripotent stem cells (hiPSCs) from patients to study XLRS in a 3D retinal organoid in vitro differentiation system. This model recapitulates key features of XLRS including retinal splitting, defective retinoschisin production, outer-segment defects, abnormal paxillin turnover, and impaired ER-Golgi transportation. RS1 mutation also affects the development of photoreceptor sensory cilia and results in altered expression of other retinopathy-associated genes. CRISPR/Cas9 correction of the disease-associated C625T mutation normalizes the splitting phenotype, outer-segment defects, paxillin dynamics, ciliary marker expression, and transcriptome profiles. Likewise, mutating RS1 in control hiPSCs produces the disease-associated phenotypes. Finally, we show that the C625T mutation can be repaired precisely and efficiently using a base-editing approach. Taken together, our data establish 3D organoids as a valid disease model.

KW - CRISPR/Cas9 gene editing

KW - RS1

KW - X-linked juvenile retinoschisis

KW - induced pluripotent stem cells

KW - retinal degeneration

KW - retinal organoid

KW - retinogenesis

KW - retinoschisin

UR - http://www.scopus.com/inward/record.url?scp=85074500452&partnerID=8YFLogxK

U2 - 10.1016/j.stemcr.2019.09.010

DO - 10.1016/j.stemcr.2019.09.010

M3 - Article

C2 - 31668851

AN - SCOPUS:85074500452

SN - 2213-6711

VL - 13

SP - 906

EP - 923

JO - Stem Cell Reports

JF - Stem Cell Reports

IS - 5

ER -

Morphological and Molecular Defects in Human Three-Dimensional Retinal Organoid Model of X-Linked Juvenile Retinoschisis

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Keywords

UN SDGs

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