Stem Cell Therapies in Retinal Disorders

Aakriti Garg, Jin Yang, Winston Lee, Stephen H Tsang, Aakriti Garg, Jin Yang, Winston Lee, Stephen H Tsang

Abstract

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.

Keywords: disease modeling; gene therapy; retina; stem cells.

Conflict of interest statement

The authors declare no conflict of interest.

References

    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. doi: 10.1016/j.stem.2012.03.002.
    1. Kaplan H.J., Tezel T.H., Berger A.S., Del Priore L.V. Retinal transplantation. Chem. Immunol. 1999;73:207–219.
    1. 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. doi: 10.1038/ncb2239.
    1. 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. doi: 10.1038/nature09798.
    1. 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. doi: 10.1016/S0140-6736(12)60028-2.
    1. 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. doi: 10.1167/iovs.15-18681.
    1. 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. doi: 10.1016/S0140-6736(14)61376-3.
    1. 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. doi: 10.1126/science.1154884.
    1. 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. doi: 10.1016/j.cell.2008.03.028.
    1. Takahashi K., Okita K., Nakagawa M., Yamanaka S. Induction of pluripotent stem cells from fibroblast cultures. Nat. Protoc. 2007;2:3081–3089. doi: 10.1038/nprot.2007.418.
    1. 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. doi: 10.1016/j.cell.2007.11.019.
    1. 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. doi: 10.1002/stem.189.
    1. 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. doi: 10.1002/stem.635.
    1. 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.
    1. 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. doi: 10.1074/jbc.M113.518571.
    1. 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. doi: 10.1371/journal.pone.0018992.
    1. 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. doi: 10.1016/S2214-109X(13)70145-1.
    1. Burke T.R., Tsang S.H. Allelic and phenotypic heterogeneity in abca4 mutations. Ophthalmic Genet. 2011;32:165–174. doi: 10.3109/13816810.2011.565397.
    1. 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.
    1. 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. doi: 10.3109/08820538.2015.1115253.
    1. 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. doi: 10.1371/journal.pone.0008763.
    1. 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. doi: 10.1167/iovs.09-4504.
    1. Corneo B., Temple S. Sense and serendipity aid rpe generation. Cell Stem Cell. 2009;5:347–348. doi: 10.1016/j.stem.2009.09.011.
    1. Okamoto S., Takahashi M. Induction of retinal pigment epithelial cells from monkey ips cells. Investig. Ophthalmol. Vis. Sci. 2011;52:8785–8790. doi: 10.1167/iovs.11-8129.
    1. 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. doi: 10.1167/iovs.12-9721.
    1. Klein R., Klein B.E., Linton K.L. Prevalence of age-related maculopathy. The beaver dam eye study. Ophthalmology. 1992;99:933–943. doi: 10.1016/S0161-6420(92)31871-8.
    1. Marchetto M.C., Gage F.H. Modeling brain disease in a dish: Really? Cell Stem Cell. 2012;10:642–645. doi: 10.1016/j.stem.2012.05.008.
    1. 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. doi: 10.1016/j.preteyeres.2013.09.002.
    1. Hayden E.C. Stem cells: The growing pains of pluripotency. Nature. 2011;473:272–274. doi: 10.1038/473272a.
    1. 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. doi: 10.1016/j.stem.2010.04.009.
    1. 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. doi: 10.1093/hmg/ddu053.
    1. 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.
    1. 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. doi: 10.1016/j.stem.2012.05.009.
    1. 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. doi: 10.1038/ncomms5047.
    1. 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. doi: 10.1016/j.stemcr.2014.03.011.
    1. 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. doi: 10.1038/nature09342.
    1. 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. doi: 10.1098/rstb.2012.0292.
    1. 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. doi: 10.1016/j.stem.2009.05.005.
    1. 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. doi: 10.1016/j.stem.2009.04.005.
    1. 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. doi: 10.1126/science.1164270.
    1. Okita K., Hong H., Takahashi K., Yamanaka S. Generation of mouse-induced pluripotent stem cells with plasmid vectors. Nat. Protoc. 2010;5:418–428. doi: 10.1038/nprot.2009.231.
    1. Ito D., Okano H., Suzuki N. Accelerating progress in induced pluripotent stem cell research for neurological diseases. Ann. Neurol. 2012;72:167–174. doi: 10.1002/ana.23596.
    1. 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. doi: 10.1586/eop.13.14.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner