Next Article in Journal
May I Cut in? Gene Editing Approaches in Human Induced Pluripotent Stem Cells
Next Article in Special Issue
Use of Human Neurons Derived via Cellular Reprogramming Methods to Study Host-Parasite Interactions of Toxoplasma gondii in Neurons
Previous Article in Journal
Implications for Diverse Functions of the LINC Complexes Based on the Structure
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Stem Cell Therapies in Retinal Disorders

Jonas Children’s Vision Care, and Bernard & Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology, Columbia University Medical Center, Edward S. Harkness Eye Institute, 635 West 165th Street, Box 112, New York, NY 10032, USA
Department of Pathology & Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
Author to whom correspondence should be addressed.
Submission received: 29 November 2016 / Accepted: 19 January 2017 / Published: 2 February 2017
(This article belongs to the Special Issue Stem Cells and Regenerative Medicine)


Stem cell therapy has long been considered a promising mode of treatment for retinal conditions. While human embryonic stem cells (ESCs) have provided the precedent for regenerative medicine, the development of induced pluripotent stem cells (iPSCs) revolutionized this field. iPSCs allow for the development of many types of retinal cells, including those of the retinal pigment epithelium, photoreceptors, and ganglion cells, and can model polygenic diseases such as age-related macular degeneration. Cellular programming and reprogramming technology is especially useful in retinal diseases, as it allows for the study of living cells that have genetic variants that are specific to patients’ diseases. Since iPSCs are a self-renewing resource, scientists can experiment with an unlimited number of pluripotent cells to perfect the process of targeted differentiation, transplantation, and more, for personalized medicine. Challenges in the use of stem cells are present from the scientific, ethical, and political realms. These include transplant complications leading to anatomically incorrect placement, concern for tumorigenesis, and incomplete targeting of differentiation leading to contamination by different types of cells. Despite these limitations, human ESCs and iPSCs specific to individual patients can revolutionize the study of retinal disease and may be effective therapies for conditions currently considered incurable.

1. Introduction

Stem Cell Transplantation

Stem cell therapy has long been considered a promising mode of treatment for retinal conditions. Human embryonic stem cells (hESCs) were once considered the only promising source of replacement cells in regenerative medicine. However, hESCs are associated with numerous drawbacks, including the concomitant administration of lifelong immunosuppressive therapy and limited effectiveness. Thus, when patient-specific induced pluripotent stem cell (iPSC) therapy was developed, exploration of disease pathophysiology, novel drug development, and the possibility of stem cell therapy in retinal disorders were forever changed [1].
The retina, particularly the subretinal space, is advantageous to stem cell transplantation as the eye is relatively immune privileged. The blood–ocular barrier protects the subretinal space by antigen-specific inhibition of responses of cellular and humoral immune systems, provided that it is not physically compromised during transplantation or due to the underlying disease pathology [2]. In such cases, the immunogenicity remains a challenge in hESC-derived transplantation, but can be mitigated by the iPSC approach. The propensity for tumorigenesis—such as the formation of teratomas, as is often the case with iPSCs, which are prone to epigenetic and transcriptional aberrations [3,4]—is a recurring complication, secondary to transplantation, that can be treated with plaque brachytherapy or proton beam radiotherapy without high risk of life-threatening consequences. Additionally, the eye is easily accessible for monitoring by exam and with several high-resolution imaging modalities, without the need for tissue biopsies pre- and post-transplantation.

2. Embryonic Stem Cells (ESCs)

A landmark study of ESCs by Schwartz et al. successfully transplanted 5 × 104 human ESC-derived retinal pigment epithelial (RPE) cells into one eye of two patients with two different forms of macular degeneration, dry age-related macular degeneration (AMD) and advanced Stargardt macular dystrophy. The initial report found that human ESC-derived RPE cells showed no signs of rejection, ectopic tissue formation, tumorigenicity, or hyperproliferation 4 months after transplantation [5]. Further preliminary results from phase 1/2 in 18 patients (9 Stargardt; 9 AMD) confirmed long-term safety and graft survival with adverse events in several patients limited to the surgical procedure or immunosuppressive regimen [6]. The authors reported increases in various functional endpoints, such as best-corrected visual acuity and quality-of-life measures, but acknowledged the need for more rigorous structure–functional relationships with clinical tests such as microperimetry, autofluorescence imaging, and optical coherence tomography scanning [6,7].
Methods for generating a master cell bank of human embryonic cell stems are detailed as follows from the previously mentioned study by Schwartz et al. [5]. This study used human ESC line Ma09 cells, which is classified as an allotransplantation. In the Schwartz et al. trial, human ESC differentiation resulted in greater than 99% pure RPE, with markers of pluripotency such as octamer-binding transcription factor 4 (OCT4), NANOG, and sex-determining region Y-box 2 (SOX2) substantially downregulated, and paired box 6 (PAX6) and RPE markers (RPE65, bestrophin 1 (BEST1), and microphthalmia-associated transcription factor (MITF)) significantly more highly expressed [5].

3. Induced Pluripotent Stem Cells (iPSCs)

The development of iPSCs allowed for a source of retinal cells for transplantation, much more cost-effective methods of drug testing, and the development of models that, at times, mimic human disease better than animal models, which do not always have physiology that is comparable to humans.
In 2007, Takahashi et al. published a method describing the creation of iPSCs, skin fibroblasts were first transduced with viral constructs expressing four transcription factors—OCT4, SOX2, Krüppel-like factor 4 (KLF4), and C-MYC [8,9,10,11]—that allowed mature cells to return to a pluripotent state similar to that seen in ESCs [10].

4. Success of iPSCs

Following the paradigm of all translational research, preclinical efficacy of iPSCs must be proven prior to use in human trials. Studies of RPE-based disorders have been shown to be the best candidates for iPSC modeling, given accessibility through manual dissection and expansion on an assortment of substrates, behavior that mimics primary human prenatal in vitro, as well as ease of monitoring of maturation state through distinct morphological features [12,13].
Novel treatment approaches have also been promising. The methods of a recent study by Li et al. on the transplantation of iPSC-derived RPE cells are as follows. Skin biopsy had been performed to obtain fibroblasts, which were subsequently cocultured with mitomycin-C-treated PA6 feeder cells, which possess stromal-derived inducing activity (SIDA) and promote RPE differentiation. As described by Takahashi et al., vectors carrying transcription factors OCT4, SOX2, KLF4, and MYC were used to reprogram cells [10,14]. Morphology and function of iPSCs was characterized by immunohistochemistry, electron microscopy, and functional analysis. iPSC-derived RPE cells were grafted subretinally into the subretinal space of mouse eyes. This study found that human iPSC-derived RPE cells were successful in restoring retinal function, as assessed by electroretinography in a mouse possessing the mutation in a gene known to be responsible for certain types of retinitis pigmentosa (RP) [14].
Maeda et al.’s group found that in comparison to isolated wild-type mouse primary RPE (mpRPE) cells, iPSC-RPE cells maintained expression of certain visual cycle proteins during cell culture, while mpRPE cells rapidly lost this trait. Specifically, iPSC-RPE cells produced the visual chromophore, 11-cis-retinal, and formed retinosomes in vitro. Further, visual function was recovered when iPSC-RPE cells were transplanted into both blind Lrat−/− and Rpe65−/− mice. Additionally, iPSC-RPE cells were found to replace dysfunctional RPE cells on histological analysis. Thus, a functional visual cycle was exhibited in vitro and in vivo by iPSC-RPE cells [15]. Further, it is no surprise that studies of retinitis pigmentosa in animal models using iPSC transplants have shown success in several studies. Additionally, improved visual-guided behaviors were noted for 6 weeks after transplantation in another preclinical RP model that received iPSC-derived photoreceptor transplants [16].

5. Stem Cells and Retinal Conditions

Retinal degenerative diseases such as age-related macular degeneration, Stargardt disease, and retinitis pigmentosa, are phenotypically diverse but have shown significant promise in being treated with iPSCs. Age-related macular degeneration, the leading cause of blindness worldwide in those above age 55 years, currently affects 1.75 million people in the USA and will affect nearly 196 million people worldwide by 2020 [17]. Stargardt disease is the most prevalent inherited macular dystrophy and is the leading cause of juvenile macular degeneration, with a prevalence of 1 in 8000–10,000 [18]. The term retinitis pigmentosa encompasses a heterogenous group of progressive retinal degenerative disorders with a worldwide prevalence of 1 in 3500–5000 individuals [19]. These and many other currently untreatable retinal conditions are the subject of many clinical trials using iPSCs to perform RPE transplantation [20].
The role of iPSCs in treatment of retinal conditions lies in their success in creating the makeup of the retina. Many types of retinal cells, including those of the RPE, photoreceptors, and ganglion cells, have been differentiated from iPSCs [21,22]. RPE cells are monolayers with pigment, making them easier to purify and isolate than other types of cells [23]; they were thus the first types of retinal cells to be differentiated from iPSCs.
Preclinical testing became possible with the development of iPSC cell lines from monkeys and subsequent differentiation into RPE cells [24]. The genetic similarities between humans and nonhuman primates allowed for the testing of the safety and efficacy of iPSC cells in vivo, using techniques that are to be employed in clinical trials. Additionally, the possibility of immune rejection was examined. Flow cytometry-based assays have shown that phagocytosis of iPSC-derived RPE is comparable in function to those found in RPE cell lines ARPE-19 and human fetal RPE (hfRPE] [25]. Future directions in retinal cell development include the growth of iPSC-derived photoreceptors and ganglion cells.
iPSCs play a significant role in the development of animal models of conditions that involve not only one gene, but many. These polygenic diseases include age-related macular degeneration, which is the leading case of irreversible blindness in the world [26].

6. Modeling Retinal Diseases in a Dish

Disease modeling in a dish provides numerous advantages over traditional human disease research, ranging from epidemiology to animal model experiments. Obstacles inherent to these conventional methods include limited availability of human tissue samples, inability to immortalize and manipulate cells while still maintaining their true physiologic properties, and variation between human diseases and their animal models [1]. The study of retinal disease poses unique challenges that arguably makes these conditions even more difficult to study. In retinal disease, like neurological disease, cell purification and cell development are difficult to study because affected tissue is not readily available. This makes cellular programming and reprogramming technology (CPART) especially useful, as modeling diseases in this manner allows for the study of living cells that have genetic variants and background that are specific to patients’ specific diseases [27].
Current retinal differentiation protocols for iPSCs can be divided into two categories, default differentiation and directed differentiation. In the first, cells are cultured in the absence of extrinsic growth factors, while in the second, differentiation is dependent on the addition of extrinsic transcription factors, small molecules, and proteins. Choice of protocol is dependent on purification goals and research aims, as no differentiation protocol provides complete efficiency in the production of retinal cells [28].
The underlying assumption in modeling diseases in vitro is that cellular deficiencies are measurable in this state and can recreate the phenotype that is demonstrated in human diseases. The concern here lies in the fact that many diseases are too variable in phenotype to be recreated in a meaningful way [27]. Such variation is particularly evident in iPSC lines.
Mechanisms of variation include variable expression profiles, female line X-inactivation, genetic instability, partial reprogramming, retention of epigenetic marks, and differentiation potential [29]. Teratoma formation is considered the gold standard criterion for the validation of pluripotency, but is not without flaws. It is considered difficult to standardize, primarily qualitative, and has questionable value in the modeling of in vitro disease [30].
Efforts to decrease variation naturally include increasing sample size. This would include creating disease team consortiums and increasing the number of analyzed patients and controls. Additionally, creating cohorts of patients who respond similarly to drugs and present with similar forms of diseases would allow for more specialized study [27]. The fact that iPSCs are a self-renewing resource will allow for the accumulation of this large sample size; scientists can experiment with an unlimited number of pluripotent cells to perfect the process of targeted differentiation, transplantation, and more, for personalized medicine [1].
A recent study by Yang et al. has showed a role for iPSCs in the determination of pathophysiology in age-related macular degeneration, which is characterized by the loss of RPE cells. iPSCs derived from the cells of patients with age-related macular degeneration allowed these scientists to analyze the downregulatory action of the age-related maculopathy susceptibility 2/high-temperature requirement A serine peptidase [ARMS2/HTRA1) risk alleles on superoxide dismutase 2 (SOD2) defense, which they found may be ultimately responsible for oxidative damage to the RPE [31].

7. Limitations of Stem Cell Use

Research with hESC has proven to be challenging, both from a scientific, ethical, and political perspective.
There are also several complications of iPSC transplants. Integration requires that grafted photoreceptors assume the correct orientation, in which an inner synapse and an outer photoreceptive segment are positioned against host inner retina and RPE, respectively. Several groups have demonstrated successfully overcoming this obstacle. Eiraku et al. developed a three-dimensional multilayered autonomous optic cup containing both rods and cones that spontaneously curves in an apically convex configuration [32,33]. Additionally, Zhong et al. created retinal cups containing all major cell types in proper configuration and were able to demonstrate the beginning of outer-segment disc formation and photosensitivity [34]. Further, Assawachananont et al. were able to successfully demonstrate retinal sheet transplantation therapy by grafting outer nuclear layer in an advanced retinal degeneration model [35].
Other complications include gliosis hampering transplantation into the retina as well as epigenetic profile, DNA sequence, and copy number heterogeneity between cell lines produced at different laboratories [36]. The latter may be ameliorated by utilizing a combination of reprogramming transcription factors or adjusting DNA methylation status that allow for the quality and heterogeneity of iPSC lines [37].
Of significant concern in iPSC use is tumorigenesis due to the persistence of undifferentiated iPSCs at the end of reprogramming and differentiation protocol. The extension of this procedure has helped to address these concerns, as none of the mice received transplants under the new protocol developed tumors throughout their lifetimes [14]. Additionally, the chances of tumorigenesis has been greatly reduced with the advent of novel gene transfer methods, which include membrane-permeable peptides [38,39] and episomal plasmids [40,41], which are not integrated into the genome [42]. These advancements corroborate the safety of the transplantation of iPSC grafts.
Lastly, the pluripotency of iPSCs is their greatest strength, but can also be viewed as their principal disadvantage, as isolating and identifying desired cell types is challenging. If targeted differentiation is not achieved, experiments can be confounded by unwanted cell types that have contaminated the same dish [43]. As mentioned in the next section, no current differentiation protocol has achieved complete fidelity [28].

8. Conclusions

Human ESCs and iPSCs specific to individual patients are a beneficial tool for the study of retinal disease and may be effective therapies for conditions currently considered incurable. Minimizing the chances of tumorigenicity and precisely targeting differentiation are the most significant challenges that must be overcome in order to make iPSC therapy a reality to treat RPE-related disorders. Ultimately, being able to model retinal conditions in vitro allows for the study of the cell development that is truly personalized to patients’ disease-specific genetic variants.


Jonas Children’s Vision Care, and Bernard & Shirlee Brown Glaucoma Laboratory are supported by the National Institute of Health [5P30EY019007, R01EY018213, R01EY024698, R01EY026682, R21AG050437], National Cancer Institute Core [5P30CA013696], the Research to Prevent Blindness (RPB) Physician-Scientist Award, unrestricted funds from RPB, New York, NY, USA. S.H.T. is a member of the RD-CURE Consortium and is supported by the Tistou and Charlotte Kerstan Foundation, the Schneeweiss Stem Cell Fund, New York State [C029572], the Foundation Fighting Blindness New York Regional Research Center Grant [C-NY05-0705-0312], the Crowley Family Fund, and the Gebroe Family Foundation.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Young, M.A.; Larson, D.E.; Sun, C.W.; George, D.R.; Ding, L.; Miller, C.A.; Lin, L.; Pawlik, K.M.; Chen, K.; Fan, X.; et al. Background mutations in parental cells account for most of the genetic heterogeneity of induced pluripotent stem cells. Cell Stem Cell 2012, 10, 570–582. [Google Scholar] [CrossRef] [PubMed]
  2. Kaplan, H.J.; Tezel, T.H.; Berger, A.S.; Del Priore, L.V. Retinal transplantation. Chem. Immunol. 1999, 73, 207–219. [Google Scholar] [PubMed]
  3. Ohi, Y.; Qin, H.; Hong, C.; Blouin, L.; Polo, J.M.; Guo, T.; Qi, Z.; Downey, S.L.; Manos, P.D.; Rossi, D.J.; et al. Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human ips cells. Nat. Cell Biol. 2011, 13, 541–549. [Google Scholar] [CrossRef] [PubMed]
  4. Lister, R.; Pelizzola, M.; Kida, Y.S.; Hawkins, R.D.; Nery, J.R.; Hon, G.; Antosiewicz-Bourget, J.; O’Malley, R.; Castanon, R.; Klugman, S.; et al. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 2011, 471, 68–73. [Google Scholar] [CrossRef] [PubMed]
  5. Schwartz, S.D.; Hubschman, J.P.; Heilwell, G.; Franco-Cardenas, V.; Pan, C.K.; Ostrick, R.M.; Mickunas, E.; Gay, R.; Klimanskaya, I.; Lanza, R. Embryonic stem cell trials for macular degeneration: A preliminary report. Lancet 2012, 379, 713–720. [Google Scholar] [CrossRef]
  6. Schwartz, S.D.; Tan, G.; Hosseini, H.; Nagiel, A. Subretinal transplantation of embryonic stem cell-derived retinal pigment epithelium for the treatment of macular degeneration: An assessment at 4 years. Investig. Ophthalmol. Vis. Sci. 2016, 57, ORSFc1–ORSFc9. [Google Scholar] [CrossRef] [PubMed]
  7. Schwartz, S.D.; Regillo, C.D.; Lam, B.L.; Eliott, D.; Rosenfeld, P.J.; Gregori, N.Z.; Hubschman, J.P.; Davis, J.L.; Heilwell, G.; Spirn, M.; et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and stargardt’s macular dystrophy: Follow-up of two open-label phase 1/2 studies. Lancet 2015, 385, 509–516. [Google Scholar] [CrossRef]
  8. Aoi, T.; Yae, K.; Nakagawa, M.; Ichisaka, T.; Okita, K.; Takahashi, K.; Chiba, T.; Yamanaka, S. Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science 2008, 321, 699–702. [Google Scholar] [CrossRef] [PubMed]
  9. Hanna, J.; Markoulaki, S.; Schorderet, P.; Carey, B.W.; Beard, C.; Wernig, M.; Creyghton, M.P.; Steine, E.J.; Cassady, J.P.; Foreman, R.; et al. Direct reprogramming of terminally differentiated mature b lymphocytes to pluripotency. Cell 2008, 133, 250–264. [Google Scholar] [CrossRef] [PubMed]
  10. Takahashi, K.; Okita, K.; Nakagawa, M.; Yamanaka, S. Induction of pluripotent stem cells from fibroblast cultures. Nat. Protoc. 2007, 2, 3081–3089. [Google Scholar] [CrossRef] [PubMed]
  11. Takahashi, K.; Tanabe, K.; Ohnuki, M.; Narita, M.; Ichisaka, T.; Tomoda, K.; Yamanaka, S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007, 131, 861–872. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Buchholz, D.E.; Hikita, S.T.; Rowland, T.J.; Friedrich, A.M.; Hinman, C.R.; Johnson, L.V.; Clegg, D.O. Derivation of functional retinal pigmented epithelium from induced pluripotent stem cells. Stem Cells 2009, 27, 2427–2434. [Google Scholar] [CrossRef] [PubMed]
  13. Kokkinaki, M.; Sahibzada, N.; Golestaneh, N. Human induced pluripotent stem-derived retinal pigment epithelium (RPE) cells exhibit ion transport, membrane potential, polarized vascular endothelial growth factor secretion, and gene expression pattern similar to native RPE. Stem Cells 2011, 29, 825–835. [Google Scholar] [CrossRef] [PubMed]
  14. Li, Y.; Tsai, Y.T.; Hsu, C.W.; Erol, D.; Yang, J.; Wu, W.H.; Davis, R.J.; Egli, D.; Tsang, S.H. Long-term safety and efficacy of human induced pluripotent stem cell (iPS) grafts in a preclinical model of retinitis pigmentosa. Mol. Med. 2012, 18, 1312–1319. [Google Scholar] [PubMed]
  15. Maeda, T.; Lee, M.J.; Palczewska, G.; Marsili, S.; Tesar, P.J.; Palczewski, K.; Takahashi, M.; Maeda, A. Retinal pigmented epithelial cells obtained from human induced pluripotent stem cells possess functional visual cycle enzymes in vitro and in vivo. J. Biol. Chem. 2013, 288, 34484–34493. [Google Scholar] [CrossRef] [PubMed]
  16. Tucker, B.A.; Park, I.H.; Qi, S.D.; Klassen, H.J.; Jiang, C.; Yao, J.; Redenti, S.; Daley, G.Q.; Young, M.J. Transplantation of adult mouse ips cell-derived photoreceptor precursors restores retinal structure and function in degenerative mice. PLoS ONE 2011, 6, e18992. [Google Scholar] [CrossRef] [PubMed]
  17. Wong, W.L.; Su, X.; Li, X.; Cheung, C.M.; Klein, R.; Cheng, C.Y.; Wong, T.Y. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: A systematic review and meta-analysis. Lancet Glob. Health 2014, 2, e106–e116. [Google Scholar] [CrossRef]
  18. Burke, T.R.; Tsang, S.H. Allelic and phenotypic heterogeneity in abca4 mutations. Ophthalmic Genet. 2011, 32, 165–174. [Google Scholar] [CrossRef] [PubMed]
  19. Chizzolini, M.; Galan, A.; Milan, E.; Sebastiani, A.; Costagliola, C.; Parmeggiani, F. Good epidemiologic practice in retinitis pigmentosa: From phenotyping to biobanking. Curr. Genomics 2011, 12, 260–266. [Google Scholar] [PubMed]
  20. Sachdeva, M.M.; Eliott, D. Stem cell-based therapy for diseases of the retinal pigment epithelium: From bench to bedside. Semin. Ophthalmol. 2016, 31, 25–29. [Google Scholar] [CrossRef] [PubMed]
  21. Lamba, D.A.; McUsic, A.; Hirata, R.K.; Wang, P.R.; Russell, D.; Reh, T.A. Generation, purification and transplantation of photoreceptors derived from human induced pluripotent stem cells. PLoS ONE 2010, 5, e8763. [Google Scholar] [CrossRef] [PubMed]
  22. Chen, M.; Chen, Q.; Sun, X.; Shen, W.; Liu, B.; Zhong, X.; Leng, Y.; Li, C.; Zhang, W.; Chai, F.; et al. Generation of retinal ganglion-like cells from reprogrammed mouse fibroblasts. Investig. Ophthalmol. Vis. Sci. 2010, 51, 5970–5978. [Google Scholar] [CrossRef] [PubMed]
  23. Corneo, B.; Temple, S. Sense and serendipity aid rpe generation. Cell Stem Cell 2009, 5, 347–348. [Google Scholar] [CrossRef] [PubMed]
  24. Okamoto, S.; Takahashi, M. Induction of retinal pigment epithelial cells from monkey ips cells. Investig. Ophthalmol. Vis. Sci. 2011, 52, 8785–8790. [Google Scholar] [CrossRef] [PubMed]
  25. Westenskow, P.D.; Moreno, S.K.; Krohne, T.U.; Kurihara, T.; Zhu, S.; Zhang, Z.N.; Zhao, T.; Xu, Y.; Ding, S.; Friedlander, M. Using flow cytometry to compare the dynamics of photoreceptor outer segment phagocytosis in iPS-derived RPE cells. Investig. Ophthalmol. Vis. Sci. 2012, 53, 6282–6290. [Google Scholar] [CrossRef] [PubMed]
  26. Klein, R.; Klein, B.E.; Linton, K.L. Prevalence of age-related maculopathy. The beaver dam eye study. Ophthalmology 1992, 99, 933–943. [Google Scholar] [CrossRef]
  27. Marchetto, M.C.; Gage, F.H. Modeling brain disease in a dish: Really? Cell Stem Cell 2012, 10, 642–645. [Google Scholar] [CrossRef] [PubMed]
  28. Borooah, S.; Phillips, M.J.; Bilican, B.; Wright, A.F.; Wilmut, I.; Chandran, S.; Gamm, D.; Dhillon, B. Using human induced pluripotent stem cells to treat retinal disease. Prog. Retin. Eye Res. 2013, 37, 163–181. [Google Scholar] [CrossRef] [PubMed]
  29. Hayden, E.C. Stem cells: The growing pains of pluripotency. Nature 2011, 473, 272–274. [Google Scholar] [CrossRef] [PubMed]
  30. Muller, F.J.; Goldmann, J.; Loser, P.; Loring, J.F. A call to standardize teratoma assays used to define human pluripotent cell lines. Cell Stem Cell 2010, 6, 412–414. [Google Scholar] [CrossRef] [PubMed]
  31. Yang, J.; Li, Y.; Chan, L.; Tsai, Y.T.; Wu, W.H.; Nguyen, H.V.; Hsu, C.W.; Li, X.; Brown, L.M.; Egli, D.; et al. Validation of GWAS alleles with patient-specific stem cell lines. Hum. Mol. Genet. 2014, 23, 3445–3455. [Google Scholar] [CrossRef] [PubMed]
  32. Eiraku, M.; Takata, N.; Ishibashi, H.; Kawada, M.; Sakakura, E.; Okuda, S.; Sekiguchi, K.; Adachi, T.; Sasai, Y. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 2011, 472, 51–56. [Google Scholar] [PubMed]
  33. Nakano, T.; Ando, S.; Takata, N.; Kawada, M.; Muguruma, K.; Sekiguchi, K.; Saito, K.; Yonemura, S.; Eiraku, M.; Sasai, Y. Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell 2012, 10, 771–785. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Zhong, X.; Gutierrez, C.; Xue, T.; Hampton, C.; Vergara, M.N.; Cao, L.H.; Peters, A.; Park, T.S.; Zambidis, E.T.; Meyer, J.S.; et al. Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Nat. Commun. 2014, 5, 4047. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Assawachananont, J.; Mandai, M.; Okamoto, S.; Yamada, C.; Eiraku, M.; Yonemura, S.; Sasai, Y.; Takahashi, M. Transplantation of embryonic and induced pluripotent stem cell-derived 3d retinal sheets into retinal degenerative mice. Stem Cell Rep. 2014, 2, 662–674. [Google Scholar] [CrossRef] [PubMed]
  36. Kim, K.; Doi, A.; Wen, B.; Ng, K.; Zhao, R.; Cahan, P.; Kim, J.; Aryee, M.J.; Ji, H.; Ehrlich, L.I.; et al. Epigenetic memory in induced pluripotent stem cells. Nature 2010, 467, 285–290. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Watanabe, A.; Yamada, Y.; Yamanaka, S. Epigenetic regulation in pluripotent stem cells: A key to breaking the epigenetic barrier. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2013, 368, 20120292. [Google Scholar] [CrossRef] [PubMed]
  38. Kim, D.; Kim, C.H.; Moon, J.I.; Chung, Y.G.; Chang, M.Y.; Han, B.S.; Ko, S.; Yang, E.; Cha, K.Y.; Lanza, R.; et al. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 2009, 4, 472–476. [Google Scholar] [CrossRef] [PubMed]
  39. Zhou, H.; Wu, S.; Joo, J.Y.; Zhu, S.; Han, D.W.; Lin, T.; Trauger, S.; Bien, G.; Yao, S.; Zhu, Y.; et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 2009, 4, 381–384. [Google Scholar] [CrossRef] [PubMed]
  40. Okita, K.; Nakagawa, M.; Hyenjong, H.; Ichisaka, T.; Yamanaka, S. Generation of mouse induced pluripotent stem cells without viral vectors. Science 2008, 322, 949–953. [Google Scholar] [CrossRef] [PubMed]
  41. Okita, K.; Hong, H.; Takahashi, K.; Yamanaka, S. Generation of mouse-induced pluripotent stem cells with plasmid vectors. Nat. Protoc. 2010, 5, 418–428. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Ito, D.; Okano, H.; Suzuki, N. Accelerating progress in induced pluripotent stem cell research for neurological diseases. Ann. Neurol. 2012, 72, 167–174. [Google Scholar] [CrossRef] [PubMed]
  43. Gamm, D.M.; Phillips, M.J.; Singh, R. Modeling retinal degenerative diseases with human iPS-derived cells: Current status and future implications. Expert Rev. Ophthalmol. 2013, 8, 213–216. [Google Scholar] [CrossRef] [PubMed]

Share and Cite

MDPI and ACS Style

Garg, A.; Yang, J.; Lee, W.; Tsang, S.H. Stem Cell Therapies in Retinal Disorders. Cells 2017, 6, 4.

AMA Style

Garg A, Yang J, Lee W, Tsang SH. Stem Cell Therapies in Retinal Disorders. Cells. 2017; 6(1):4.

Chicago/Turabian Style

Garg, Aakriti, Jin Yang, Winston Lee, and Stephen H. Tsang. 2017. "Stem Cell Therapies in Retinal Disorders" Cells 6, no. 1: 4.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop