Development of Retinal Pigment Epithelium from Human Parthenogenetic Embryonic Stem Cells and MicroRNA Signature

Li, Wenbo; Zhang, Yunshan; Lu, Zhenyu; Dong, Lijie; Wang, Fei E.; Dong, Rong; Li, Xiaorong

doi:10.1167/iovs.12-8303

Cited by 32 publications

(23 citation statements)

References 37 publications

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“…A large body of evidence indicates that miR-204 plays a crucial role in the differentiation and function of all of the ocular structures in which it is expressed. In vitro assays have shown that miR-204 may be involved in the correct differentiation and function of RPE cells (27,29,30). MiR-204 is also required for proper lens development (9,10).…”

Section: Discussionmentioning

confidence: 99%

MiR-204 is responsible for inherited retinal dystrophy associated with ocular coloboma

Conte

Hadfield

Barbato

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

100

111

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Ocular developmental disorders, including the group classified as microphthalmia, anophthalmia, and coloboma (MAC) and inherited retinal dystrophies, collectively represent leading causes of hereditary blindness. Characterized by extreme genetic and clinical heterogeneity, the separate groups share many common genetic causes, in particular relating to pathways controlling retinal and retinal pigment epithelial maintenance. To understand these shared pathways and delineate the overlap between these groups, we investigated the genetic cause of an autosomal dominantly inherited condition of retinal dystrophy and bilateral coloboma, present in varying degrees in a large, five-generation family. By linkage analysis and exome sequencing, we identified a previously undescribed heterozygous mutation, n.37C > T, in the seed region of microRNA-204 (miR-204), which segregates with the disease in all affected individuals. We demonstrated that this mutation determines significant alterations of miR-204 targeting capabilities via in vitro assays, including transcriptome analysis. In vivo injection, in medaka fish (Oryzias latipes), of the mutated miR-204 caused a phenotype consistent with that observed in the family, including photoreceptor alterations with reduced numbers of both cones and rods as a result of increased apoptosis, thereby confirming the pathogenic effect of the n.37C > T mutation. Finally, knockdown assays in medaka fish demonstrated that miR-204 is necessary for normal photoreceptor function. Overall, these data highlight the importance of miR-204 in the regulation of ocular development and maintenance and provide the first evidence, to our knowledge, of its contribution to eye disease, likely through a gain-of-function mechanism.

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Section: Discussionmentioning

confidence: 99%

MiR-204 is responsible for inherited retinal dystrophy associated with ocular coloboma

Conte

Hadfield

Barbato

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

100

111

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“…Mitf also transactivates expression of miRNAs, and the dynamic regulation of miRNA expression is strongly associated with RPE differentiation; e.g. miR-204 and miR-211 (Adijanto et al, 2012; Hu et al, 2012; Li et al, 2012; Wang et al, 2010a). …”

Section: Overview Of Early Eye Development and Rpe Specificationmentioning

confidence: 99%

Retinal pigment epithelium development, plasticity, and tissue homeostasis

Fuhrmann

Zou

Levine

2014

Experimental Eye Research

217

162

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The retinal pigment epithelium (RPE) is a simple epithelium interposed between the neural retina and the choroid. Although only 1 cell-layer in thickness, the RPE is a virtual workhorse, acting in several capacities that are essential for visual function and preserving the structural and physiological integrities of neighboring tissues. Defects in RPE function, whether through chronic dysfunction or age-related decline, are associated with retinal degenerative diseases including age-related macular degeneration. As such, investigations are focused on developing techniques to replace RPE through stem cell-based methods, motivated primarily because of the seemingly limited regeneration or self-repair properties of mature RPE. Despite this, RPE cells have an unusual capacity to transdifferentiate into various cell types, with the particular fate choices being highly context-dependent. In this review, we describe recent findings elucidating the mechanisms and steps of RPE development and propose a developmental framework for understanding the apparent contradiction in the capacity for low self-repair versus high transdifferentiation.

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“…Complexity in the regulatory network between miRNAs and their processing factors has, to certain extents, limits comprehensive and thorough investigations. MiRNAs’ roles in the survival and function of RPE cells have been previously annotated, while their roles in RPE differentiation are still unclear [15, 16]. MiR-184 , located on 15q25.1, is an evolutionarily conserved non-coding RNA oligo.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-184 promotes differentiation of the retinal pigment epithelium by targeting the AKT2/mTOR signaling pathway

Jiang

Qin

et al. 2016

Oncotarget

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Dedifferentiation of retinal pigment epithelium (RPE) cells is a crucial contributing factor to the pathology of retinal degenerative diseases, including age-related macular degeneration (AMD). Herein, we aim to reveal the roles of microRNAs (miRNAs) in RPE dedifferentiation and seek for potential therapeutic targets. Based on the microarray data, miR-184 was sorted out as the most up-regulated signature along with the differentiation from human induced pluripotent stem cells (hiPSC) to RPE cells, suggesting its potential promotive role in RPE differentiation. In vitro study indicated that miR-184 insufficiency suppressed RPE differentiation, typified by reduction of RPE markers, and promoted cell proliferation and migration. The role of miR-184 in maintaining regular RPE function was further proved in zebrafish studies. We also noticed that miR-184 expression was reduced in the macular RPE-choroid from a donor with RPE dysfunction compared to a healthy control. We next demonstrated that RAC-beta serine/threonine-protein kinase (AKT2) was a direct target for miR-184. MiR-184 promoted RPE differentiation via suppression of AKT2/mammalian target of rapamycin (mTOR) signaling pathway. We also found that AKT2 was up-regulated in macular RPE-choroid of the donor with RPE dysfunction and dry AMD patients. Taken together, our findings suggest that miR-184 insufficiency is involved in the pathogenesis of dry AMD. MiR-184 promotes RPE differentiation via inhibiting the AKT2/mTOR signaling pathway. MiR-184 based supplementary therapeutics and mTOR blocker, like rapamycin, are prospective options for AMD treatment.

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Development of Retinal Pigment Epithelium from Human Parthenogenetic Embryonic Stem Cells and MicroRNA Signature

Cited by 32 publications

References 37 publications

MiR-204 is responsible for inherited retinal dystrophy associated with ocular coloboma

MiR-204 is responsible for inherited retinal dystrophy associated with ocular coloboma

Retinal pigment epithelium development, plasticity, and tissue homeostasis

MicroRNA-184 promotes differentiation of the retinal pigment epithelium by targeting the AKT2/mTOR signaling pathway

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