Stem Cell Derived Retinal Pigment Epithelium: The Role of Pigmentation as Maturation Marker and Gene Expression Profile Comparison with Human Endogenous Retinal Pigment Epithelium.

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

In age-related macular degeneration (AMD) the retinal pigment epithelium (RPE) deteriorates, leading to photoreceptor decay and severe vision loss. New therapeutic strategies aim at RPE replacement by transplantation of pluripotent stem cell (PSC)-derived RPE. Several protocols to generate RPE have been developed where appearance of pigmentation is commonly used as indicator of RPE differentiation and maturation. It is, however, unclear how different pigmentation stages reflect developmental stages and functionality of PSC-derived RPE cells. We generated human embryonic stem cell-derived RPE (hESC-RPE) cells and investigated their gene expression profiles at early pigmentation (EP) and late pigmentation (LP) stages. In addition, we compared the hESC-RPE samples with human endogenous RPE. We used a common reference design microarray (44 K). Our analysis showed that maturing hESC-RPE, upon acquiring pigmentation, expresses markers specific for human RPE. Interestingly, our analysis revealed that EP and LP hESC-RPE do not differ much in gene expression. Our data further showed that pigmented hESC-RPE has a significant lower expression than human endogenous RPE in the visual cycle and oxidative stress pathways. In contrast, we observed a significantly higher expression of pathways related to the process adhesion-to-polarity model that is typical of developing epithelial cells. We conclude that, in vitro, the first appearance of pigmentation hallmarks differentiated RPE. However, further increase in pigmentation does not result in much significant gene expression changes and does not add important RPE functionalities. Consequently, our results suggest that the time span for obtaining differentiated hESC-RPE cells, that are suitable for transplantation, may be greatly reduced.

Electronic supplementary material

The online version of this article (doi:10.1007/s12015-017-9754-0) contains supplementary material, which is available to authorized users.

Related collections

Most cited references 33

Record: found
Abstract: found
Article: not found

Directed differentiation of human embryonic stem cells into functional retinal pigment epithelium cells.

Maria Idelson, Ruslana Alper, Alexey Obolensky … (2009)

Dysfunction and loss of retinal pigment epithelium (RPE) leads to degeneration of photoreceptors in age-related macular degeneration and subtypes of retinitis pigmentosa. Human embryonic stem cells (hESCs) may serve as an unlimited source of RPE cells for transplantation in these blinding conditions. Here we show the directed differentiation of hESCs toward an RPE fate under defined culture conditions. We demonstrate that nicotinamide promotes the differentiation of hESCs to neural and subsequently to RPE fate. In the presence of nicotinamide, factors from the TGF-beta superfamily, which presumably pattern RPE development during embryogenesis, further direct RPE differentiation. The hESC-derived pigmented cells exhibit the morphology, marker expression, and function of authentic RPE and rescue retinal structure and function after transplantation to an animal model of retinal degeneration caused by RPE dysfunction. These results are an important step toward the future use of hESCs to replenish RPE in blinding diseases.

0 comments Cited 133 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Derivation and comparative assessment of retinal pigment epithelium from human embryonic stem cells using transcriptomics.

Robert Lanza, Jason Hipp, Jason D. Hipp … (2004)

Human stem-cell derivatives are likely to play an important role in the future of regenerative medicine. Evaluation and comparison to their in vivo counterparts is critical for assessment of their therapeutic potential. Transcriptomics was used to compare a new differentiation derivative of human embryonic stem (hES) cells--retinal pigment epithelium (RPE)--to human fetal RPE. Several hES cell lines were differentiated into putative RPE, which expressed RPEspecific molecular markers and was capable of phagocytosis, an important RPE function. Isolated hES cell-derived RPE was able to transdifferentiate into cells of neuronal lineage and redifferentiate into RPE-like cells through multiple passages (>30 Population doublings). Gene expression profiling demonstrated their higher similarity to primary RPE tissue than of existing human RPE cell lines D407 and ARPE-19, which has been shown to attenuate loss of visual function in animals. This is the first report of the isolation and characterization of putative RPE cells from hES cells, as well as the first application of transcriptomics to assess embryonic stem-cell derivatives and their in vivo counterparts--a "differentiomics" outlook. We describe for the first time, a differentiation system that does not require coculture with animal cells or factors, thus allowing the production of zoonoses-free RPE cells suitable for subretinal transplantation in patients with retinal degenerative diseases. With the further development of therapeutic cloning, or the creation of the banks of homozygous human leucocyte antigen (HLA) hES cells using parthenogenesis, RPE lines could be generated to overcome the problem of immune rejection and could be one of the nearest term applications of stem-cell technology.

0 comments Cited 98 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Human embryonic stem cell-derived cells rescue visual function in dystrophic RCS rats.

Robert Lanza, Irina Klimanskaya, Sergej Girman … (2005)

Embryonic stem cells promise to provide a well-characterized and reproducible source of replacement tissue for human clinical studies. An early potential application of this technology is the use of retinal pigment epithelium (RPE) for the treatment of retinal degenerative diseases such as macular degeneration. Here we show the reproducible generation of RPE (67 passageable cultures established from 18 different hES cell lines); batches of RPE derived from NIH-approved hES cells (H9) were tested and shown capable of extensive photoreceptor rescue in an animal model of retinal disease, the Royal College of Surgeons (RCS) rat, in which photoreceptor loss is caused by a defect in the adjacent retinal pigment epithelium. Improvement in visual performance was 100% over untreated controls (spatial acuity was approximately 70% that of normal nondystrophic rats) without evidence of untoward pathology. The use of somatic cell nuclear transfer (SCNT) and/or the creation of banks of reduced complexity human leucocyte antigen (HLA) hES-RPE lines could minimize or eliminate the need for immunosuppressive drugs and/or immunomodulatory protocols.

0 comments Cited 95 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

V. M. Heine: +31205986695 , vm.heine@vumc.nl

A. A. Bergen: +31205664592 , a.bergen@amc.uva.nl

Journal

Journal ID (nlm-ta): Stem Cell Rev

Journal ID (iso-abbrev): Stem Cell Rev

Title: Stem Cell Reviews

Publisher: Springer US (New York )

ISSN (Print): 1550-8943

ISSN (Electronic): 1558-6804

Publication date (Electronic): 21 July 2017

Publication date PMC-release: 21 July 2017

Publication date (Print): 2017

Volume: 13

Issue: 5

Pages: 659-669

Affiliations

[1 ]ISNI 0000000404654431, GRID grid.5650.6, Department of Clinical Genetics, , AMC, ; Amsterdam, The Netherlands

[2 ]ISNI 0000 0001 2153 6865, GRID grid.418101.d, The Netherlands Institute for Neuroscience (NIN-KNAW), , Royal Netherlands Academy of Arts and Sciences, ; Amsterdam, The Netherlands

[3 ]ISNI 0000 0004 0435 165X, GRID grid.16872.3a, Department of Pediatrics/Child Neurology, , VU University Medical Center, ; Amsterdam, The Netherlands

[4 ]ISNI 0000000404654431, GRID grid.5650.6, Ocular Angiogenesis Group, AMC, ; Amsterdam, The Netherlands

[5 ]ISNI 0000000404654431, GRID grid.5650.6, Department of Ophthalmology, AMC, ; Amsterdam, The Netherlands

[6 ]ISNI 0000000404654431, GRID grid.5650.6, Department of Cell Biology and Histology, AMC, ; Amsterdam, The Netherlands

[7 ]ISNI 0000 0001 0009 7699, GRID grid.414699.7, Rotterdam Eye Hospital, ; Amsterdam, The Netherlands

[8 ]University Eye Clinic Maastricht, MUMC+, Amsterdam, The Netherlands

[9 ]ISNI 0000000404654431, GRID grid.5650.6, Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, AMC, ; Amsterdam, The Netherlands

[10 ]ISNI 0000 0004 1754 9227, GRID grid.12380.38, Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, , VU University Amsterdam, ; Amsterdam, The Netherlands

Article

Publisher ID: 9754

DOI: 10.1007/s12015-017-9754-0

PMC ID: 5602068

PubMed ID: 28730556

SO-VID: 0622781a-ac2b-4809-9457-dfdbaba260c9

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Funding

Funded by: Uitzicht

Award ID: 2011-6

Custom metadata

ScienceOpen disciplines: Molecular medicine

Keywords: human embryonic stem cells,retinal pigment epithelium,pigmentation,age related macular degeneration,cell replacement therapy,transcriptomics

Data availability:

ScienceOpen disciplines: Molecular medicine

Keywords: human embryonic stem cells, retinal pigment epithelium, pigmentation, age related macular degeneration, cell replacement therapy, transcriptomics

Stem Cell Derived Retinal Pigment Epithelium: The Role of Pigmentation as Maturation Marker and Gene Expression Profile Comparison with Human Endogenous Retinal Pigment Epithelium.

Read this article at

Abstract

Electronic supplementary material

Related collections

Karger: Ophthalmology

Most cited references 33

Directed differentiation of human embryonic stem cells into functional retinal pigment epithelium cells.

Derivation and comparative assessment of retinal pigment epithelium from human embryonic stem cells using transcriptomics.

Human embryonic stem cell-derived cells rescue visual function in dystrophic RCS rats.

Author and article information

Contributors

Journal

Affiliations

Article

History

Funding

Categories

Custom metadata

Comments

Comment on this article

Similar content 305

Cited by 11

Most referenced authors 455