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Retinal repair with induced pluripotent stem cells

  • Shomoukh Al-Shamekh
    Affiliations
    Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Fla

    Department of Ophthalmology, King Abdulaziz University Hospital, King Saud University, Riyadh, Saudi Arabia
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  • Jeffrey L. Goldberg
    Correspondence
    Reprint requests: Jeffrey L. Goldberg, Shiley Eye Center, 9415 Campus Point Dr. #0946, University of California, La Jolla, CA 92093
    Affiliations
    Shiley Eye Center, University of California, San Diego, Calif

    Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Fla
    Search for articles by this author
Published:November 11, 2013DOI:https://doi.org/10.1016/j.trsl.2013.11.002
      Retinal degeneration such as age-related macular degeneration and other inherited forms, such as Stargardt's disease and retinitis pigmentosa, and optic neuropathies including glaucoma and ischemic optic neuropathy are major causes of vision loss and blindness worldwide. Damage to retinal pigment epithelial cells and photoreceptors in the former, and to retinal ganglion cell axons in the optic nerve and their cell bodies in the retina in the latter diseases lead to the eventual death of these retinal cells, and in humans there is no endogenous replacement or repair. Cell replacement therapies provide 1 avenue to restore function in these diseases, particularly in the case of retinal repair, although there are considerable issues to overcome, including the differentiation and integration of the transplanted cells. What stem cell sources could be used for such therapies? One promising source is induced pluripotent stem cells (iPSCs), which could be drawn from an individual patient needing therapy, or generated and banked from select donors. We review developing research in the use of iPSCs for retinal cell replacement therapy.

      Abbreviations:

      AMD (age-related macular degeneration), BEST1 (bestrophin 1), bFGF (basic fibroblast growth factor), ECM (extracellular matrix), FACS (fluorescent-activated cell sorting), FGF (fibroblast growth factor), hESC (human embryonic stem cell), hiPSC (human induced pluripotent stem cell), IGF-1 (insulin growth factor 1), iPSC (induced pluripotent stem cell), IRBP (interphotoreceptor retinol binding protein), RA (retinoic acid), RGC (retinal ganglion cell), RP (retinitis pigmentosa), RPC (retinal progenitor cell), RPE (retinal pigment epithelium), SHH (sonic hedgehog)
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      References

      1. Purves D.A.G. Fitzpatrick D. Augustine G.J. The Retina: Neuroscience. Sinauer Associates, Sunderland, Mass2001
        • Strauss O.
        The retinal pigment epithelium in visual function.
        Physiol Rev. 2005; 85: 845-881
        • Gehrs K.M.
        • Anderson D.H.
        • Johnson L.V.
        • Hageman G.S.
        Age-related macular degeneration: emerging pathogenetic and therapeutic concepts.
        Ann Med. 2006; 38: 450-471
        • Del Priore L.V.
        • Kaplan H.J.
        Pathogenesis of AMD.
        Ophthalmology. 1995; 102: 1125-1126
        • Dunaief J.L.
        • Dentchev T.
        • Ying G.S.
        • Milam A.H.
        The role of apoptosis in age-related macular degeneration.
        Arch Ophthalmol. 2002; 120: 1435-1442
        • Barber A.C.
        • Hippert C.
        • Duran Y.
        • et al.
        Repair of the degenerate retina by photoreceptor transplantation.
        Proc Natl Acad Sci U S A. 2013; 110: 354-359
        • MacLaren R.
        • Pearson R.
        • MacNeil A.
        • et al.
        Retinal repair by transplantation of photoreceptor precursors.
        Nature. 2006; 444: 203-207
        • Hertz J.
        • Qu B.
        • Hu Y.
        • Patel R.D.
        • Valenzuela D.A.
        • Goldberg J.L.
        Survival and integration of developing and progenitor-derived retinal ganglion cells following transplantation.
        Cell Transplant. 2013;
        • Humayun M.S.
        • de Juan Jr., E.
        • del Cerro M.
        • et al.
        Human neural retinal transplantation.
        Invest Ophthalmol Vis Sci. 2000; 41: 3100-3106
        • Radtke N.D.
        • Seiler M.J.
        • Aramant R.B.
        • Petry H.M.
        • Pidwell D.J.
        Transplantation of intact sheets of fetal neural retina with its retinal pigment epithelium in retinitis pigmentosa patients.
        Am J Ophthalmol. 2002; 133: 544-550
        • Radtke N.D.
        • Aramant R.B.
        • Petry H.M.
        • Green P.T.
        • Pidwell D.J.
        • Seiler M.J.
        Vision improvement in retinal degeneration patients by implantation of retina together with retinal pigment epithelium.
        Am J Ophthalmol. 2008; 146: 172-182
        • Turner D.
        • Cepko C.
        A common progenitor for neurons and glia persists in rat retina late in development.
        Nature. 1987; 328: 131-136
        • Klassen H.
        Transplantation of cultured progenitor cells to the mammalian retina.
        Exp Opin Biol Ther. 2006; 6: 443-451
        • Young M.J.
        Stem cells in the mammalian eye: a tool for retinal repair.
        Acta Pathol Microbiol Immunol Scand. 2005; 113: 845-857
        • Bhatia B.
        • Singhal S.
        • Jayaram H.
        • Khaw P.T.
        • Limb G.A.
        Adult retinal stem cells revisited.
        Ophthalmol J. 2010; 4: 30-38
        • Blenkinsop T.A.
        • Salero E.
        • Stern J.H.
        • Temple S.
        The culture and maintenance of functional retinal pigment epithelial monolayers from adult human eye.
        Methods Mol Biol. 2013; 945: 45-65
        • Salero E.
        • Blenkinsop T.A.
        • Corneo B.
        • et al.
        Adult human RPE can be activated into a multipotent stem cell that produces mesenchymal derivatives.
        Cell Stem Cell. 2012; 10: 88-95
        • Thomson J.
        • Itskovitz-Eldor J.
        • Shapiro S.
        • et al.
        Embryonic stem cell lines derived from human blastocysts.
        Science. 1998; 282: 1145-1147
        • Lamba D.A.
        • Karl M.O.
        • Ware C.B.
        • Reh T.A.
        Efficient generation of retinal progenitor cells from human embryonic stem cells.
        Proc Natl Acad Sci U S A. 2006; 103: 12769-12774
        • Eiraku M.
        • Sasai Y.
        Mouse embryonic stem cell culture for generation of three-dimensional retinal and cortical tissues.
        Nat Prot. 2012; 7: 69-79
        • Osakada F.
        • Ikeda H.
        • Sasai Y.
        • Takahashi M.
        Stepwise differentiation of pluripotent stem cells into retinal cells.
        Nat Prot. 2009; 4: 811-824
        • Idelson M.
        • Alper R.
        • Obolensky A.
        • et al.
        Directed differentiation of human embryonic stem cells into functional retinal pigment epithelium cells.
        Cell Stem Cell. 2009; 5: 396-408
        • Vugler A.
        • Carr A.J.
        • Lawrence J.
        • et al.
        Elucidating the phenomenon of HESC-derived RPE: anatomy of cell genesis, expansion and retinal transplantation.
        Exp Neurol. 2008; 214: 347-361
        • Jagatha B.
        • Divya M.
        • Sanalkumar R.
        • et al.
        In vitro differentiation of retinal ganglion-like cells from embryonic stem cell derived neural progenitors.
        Biochem Biophys Res Commun. 2009; 380: 230-235
        • Kayama M.
        • Kurokawa M.S.
        • Ueda Y.
        • et al.
        Transfection with pax6 gene of mouse embryonic stem cells and subsequent cell cloning induced retinal neuron progenitors, including retinal ganglion cell-like cells, in vitro.
        Ophthalmic Res. 2010; 43: 79-91
        • Gamm D.M.
        • Wright L.S.
        From embryonic stem cells to mature photoreceptors.
        Nat Biotechnol. 2013; 31: 712-713
        • Subrizi A.
        • Hiidenmaa H.
        • Ilmarinen T.
        • et al.
        Generation of hESC-derived retinal pigment epithelium on biopolymer coated polyimide membranes.
        Biomaterials. 2012; 33: 8047-8054
        • Osakada F.
        • Ikeda H.
        • Mandai M.
        • et al.
        Toward the generation of rod and cone photoreceptors from mouse, monkey and human embryonic stem cells.
        Nat Biotechnol. 2008; 26: 215-224
        • Aoki H.
        • Hara A.
        • Nakagawa S.
        • et al.
        Embryonic stem cells that differentiate into RPE cell precursors in vitro develop into RPE cell monolayers in vivo.
        Exp Eye Res. 2006; 82: 265-274
        • Aoki H.
        • Hara A.
        • Niwa M.
        • Motohashi T.
        • Suzuki T.
        • Kunisada T.
        Transplantation of cells from eye-like structures differentiated from embryonic stem cells in vitro and in vivo regeneration of retinal ganglion-like cells.
        Graefes Arch Clin Exp Ophthalmol. 2008; 246: 255-265
        • Banin E.
        • Obolensky A.
        • Idelson M.
        • et al.
        Retinal incorporation and differentiation of neural precursors derived from human embryonic stem cells.
        Stem Cells. 2006; 24: 246-257
        • Gonzalez-Cordero A.
        • West E.L.
        • Pearson R.A.
        • et al.
        Photoreceptor precursors derived from three-dimensional embryonic stem cell cultures integrate and mature within adult degenerate retina.
        Nat Biotechnol. 2013; 31: 741-747
        • Hambright D.
        • Park K.-Y.
        • Brooks M.
        • McKay R.
        • Swaroop A.
        • Nasonkin I.
        Long-term survival and differentiation of retinal neurons derived from human embryonic stem cell lines in un-immunosuppressed mouse retina.
        Mol Vision. 2012; 18: 920-936
        • Lamba D.A.
        • Gust J.
        • Reh T.A.
        Transplantation of human embryonic stem cell-derived photoreceptors restores some visual function in Crx-deficient mice.
        Cell Stem Cell. 2009; 4: 73-79
        • Lund R.D.
        • Wang S.
        • Klimanskaya I.
        • et al.
        Human embryonic stem cell-derived cells rescue visual function in dystrophic RCS rats.
        Cloning Stem Cells. 2006; 8: 189-199
        • Wang N.K.
        • Tosi J.
        • Kasanuki J.M.
        • et al.
        Transplantation of reprogrammed embryonic stem cells improves visual function in a mouse model for retinitis pigmentosa.
        Transplantation. 2010; 89: 911-919
        • West E.L.
        • Gonzalez-Cordero A.
        • Hippert C.
        • et al.
        Defining the integration capacity of embryonic stem cell-derived photoreceptor precursors.
        Stem Cells. 2012; 30: 1424-1435
        • Schwartz S.
        • Hubschman J.-P.
        • Heilwell G.
        • et al.
        Embryonic stem cell trials for macular degeneration: a preliminary report.
        Lancet. 2012; 379: 713-720
        • Takahashi K.
        • Yamanaka S.
        Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.
        Cell. 2006; 126: 663-676
        • Takahashi K.
        • Tanabe K.
        • Ohnuki M.
        • et al.
        Induction of pluripotent stem cells from adult human fibroblasts by defined factors.
        Cell. 2007; 131: 861-872
        • Yu J.
        • Hu K.
        • Smuga-Otto K.
        • et al.
        Human induced pluripotent stem cells free of vector and transgene sequences.
        Science. 2009; 324: 797-801
        • Gonzalez F.
        • Barragan Monasterio M.
        • Tiscornia G.
        • et al.
        Generation of mouse-induced pluripotent stem cells by transient expression of a single nonviral polycistronic vector.
        Proc Natl Acad Sci U S A. 2009; 106: 8918-8922
        • Meir Y.J.
        • Lin A.
        • Huang M.F.
        • et al.
        A versatile, highly efficient, and potentially safer piggyBac transposon system for mammalian genome manipulations.
        FASEB J. 2013; 27: 4429-4443
        • Hou P.
        • Li Y.
        • Zhang X.
        • et al.
        Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds.
        Science. 2013; 341: 651-654
        • Li X.
        • Burnight E.R.
        • Cooney A.L.
        • et al.
        piggyBac transposase tools for genome engineering.
        Proc Natl Acad Sci U S A. 2013; 110: E2279-E2287
        • Merkl C.
        • Saalfrank A.
        • Riesen N.
        • et al.
        Efficient generation of rat induced pluripotent stem cells using a non-viral inducible vector.
        PLoS One. 2013; 8: e55170
        • Li Y.
        • Zhang Q.
        • Yin X.
        • et al.
        Generation of iPSCs from mouse fibroblasts with a single gene, Oct4, and small molecules.
        Cell Res. 2011; 21: 196-204
        • Yu J.
        • Vodyanik M.
        • Smuga-Otto K.
        • et al.
        Induced pluripotent stem cell lines derived from human somatic cells.
        Science. 2007; 318: 1917-1920
      2. http://www.riken.jp/en/pr/press/2013/20130730_1/.

        • Buchholz D.
        • Pennington B.
        • Croze R.
        • Hinman C.
        • Coffey P.
        • Clegg D.
        Rapid and efficient directed differentiation of human pluripotent stem cells into retinal pigmented epithelium.
        Stem Cell Transl Med. 2013; 2: 384-393
        • 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
        • Maruotti J.
        • Wahlin K.
        • Gorrell D.
        • Bhutto I.
        • Lutty G.
        • Zack D.
        A simple and scalable process for the differentiation of retinal pigment epithelium from human pluripotent stem cells.
        Stem Cell Transl Med. 2013; 2: 341-354
        • Hu Q.
        • Friedrich A.
        • Johnson L.
        • Clegg D.
        Memory in induced pluripotent stem cells: reprogrammed human retinal-pigmented epithelial cells show tendency for spontaneous redifferentiation.
        Stem Cells. 2010; 28: 1981-1991
        • Rowland T.
        • Blaschke A.
        • Buchholz D.
        • Hikita S.
        • Johnson L.
        • Clegg D.
        Differentiation of human pluripotent stem cells to retinal pigmented epithelium in defined conditions using purified extracellular matrix proteins.
        J Tissue Eng Regen Med. 2013; 7: 642-653
        • Carr A.-J.
        • Vugler A.
        • Hikita S.
        • et al.
        Protective effects of human iPS-derived retinal pigment epithelium cell transplantation in the retinal dystrophic rat.
        PLoS One. 2009; 4: e8152
        • Hirami Y.
        • Osakada F.
        • Takahashi K.
        • et al.
        Generation of retinal cells from mouse and human induced pluripotent stem cells.
        Neurosci Lett. 2009; 458: 126-131
        • Buchholz D.
        • Hikita S.
        • Rowland T.
        • et al.
        Derivation of functional retinal pigmented epithelium from induced pluripotent stem cells.
        Stem Cells. 2009; 27: 2427-2434
        • Osakada F.
        • Jin Z.-B.
        • Hirami Y.
        • et al.
        In vitro differentiation of retinal cells from human pluripotent stem cells by small-molecule induction.
        J Cell Sci. 2009; 122: 3169-3179
        • Meyer J.
        • Shearer R.
        • Capowski E.
        • et al.
        Modeling early retinal development with human embryonic and induced pluripotent stem cells.
        Proc Natl Acad Sci U S A. 2009; 106: 16698-16703
        • Liao J.-L.
        • Yu J.
        • Huang K.
        • et al.
        Molecular signature of primary retinal pigment epithelium and stem-cell-derived RPE cells.
        Human Mol Genet. 2010; 19: 4229-4238
        • Zahabi A.
        • Shahbazi E.
        • Ahmadieh H.
        • et al.
        A new efficient protocol for directed differentiation of retinal pigmented epithelial cells from normal and retinal disease induced pluripotent stem cells.
        Stem Cells Devel. 2012; 21: 2262-2272
        • Jin Z.-B.
        • Okamoto S.
        • Xiang P.
        • Takahashi M.
        Integration-free induced pluripotent stem cells derived from retinitis pigmentosa patient for disease modeling.
        Stem Cells Transl Med. 2012; 1: 503-509
        • Tucker B.
        • Anfinson K.
        • Mullins R.
        • Stone E.
        • Young M.
        Use of a synthetic xeno-free culture substrate for induced pluripotent stem cell induction and retinal differentiation.
        Stem Cell Transl Med. 2013; 2: 16-24
        • 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
        • Sridhar A.
        • Steward M.
        • Meyer J.
        Nonxenogeneic growth and retinal differentiation of human induced pluripotent stem cells.
        Stem Cell Transl Med. 2013; 2: 255-264
        • Meyer J.
        • Howden S.
        • Wallace K.
        • et al.
        Optic vesicle-like structures derived from human pluripotent stem cells facilitate a customized approach to retinal disease treatment.
        Stem Cells. 2011; 29: 1206-1218
        • Okamoto S.
        • Takahashi M.
        Induction of retinal pigment epithelial cells from monkey iPS cells.
        Invest Ophthalmol Vis Sci. 2011; 52: 8785-8790
        • Cimadamore F.
        • Curchoe C.L.
        • Alderson N.
        • Scott F.
        • Salvesen G.
        • Terskikh A.V.
        Nicotinamide rescues human embryonic stem cell-derived neuroectoderm from parthanatic cell death.
        Stem Cells. 2009; 27: 1772-1781
        • Jin Z.B.
        • Okamoto S.
        • Osakada F.
        • et al.
        PLoS One. 2011; 6: e17084
        • Boucherie C.
        • Mukherjee S.
        • Henckaerts E.
        • Thrasher A.
        • Sowden J.
        • Ali R.
        Brief report: self-organizing neuroepithelium from human pluripotent stem cells facilitates derivation of photoreceptors.
        Stem Cells. 2013; 31: 408-414
        • Gamm D.
        • Meyer J.
        Directed differentiation of human induced pluripotent stem cells: a retina perspective.
        Regen Med. 2010; 5: 315-317
        • Chen M.
        • Chen Q.
        • Sun X.
        • et al.
        Generation of retinal ganglion-like cells from reprogrammed mouse fibroblasts.
        Invest Ophthalmol Vis Sci. 2010; 51: 5970-5978
        • Parameswaran S.
        • Balasubramanian S.
        • Babai N.
        • et al.
        Induced pluripotent stem cells generate both retinal ganglion cells and photoreceptors: therapeutic implications in degenerative changes in glaucoma and age-related macular degeneration.
        Stem Cells. 2010; 28: 695-703
      3. Hertz J, Jin XL, Derosa BA, et al. Novel regulatory mechanisms for the SoxC transcriptional network required for visual pathway development. 2013.

        • Brown N.L.
        • Patel S.
        • Brzezinski J.
        • Glaser T.
        Math5 is required for retinal ganglion cell and optic nerve formation.
        Development. 2001; 128: 2497-2508
        • Jiang Y.
        • Ding Q.
        • Xie X.
        • Libby R.T.
        • Lefebvre V.
        • Gan L.
        Transcription factors SOX4 and SOX11 function redundantly to regulate the development of mouse retinal ganglion cells.
        J Biol Chem. 2013; 288: 18429-18438
        • Hertz J.
        • Robinson R.
        • Valenzuela D.A.
        • Lavik E.B.
        • Goldberg J.L.
        A tunable synthetic hydrogel system for culture of retinal ganglion cells and amacrine cells.
        Acta Biomater. 2013; 9: 7622-7629
        • Kador K.E.
        • Montero R.B.
        • Venugopalan P.
        • et al.
        Tissue engineering the retinal ganglion cell nerve fiber layer.
        Biomaterials. 2013; 34: 4242-4250
        • Johnson T.V.
        • Bull N.D.
        • Martin K.R.
        Neurotrophic factor delivery as a protective treatment for glaucoma.
        Exp Eye Res. 2011; 93: 196-203
        • Tucker B.A.
        • Park I.H.
        • Qi S.D.
        • et al.
        Transplantation of adult mouse iPS cell-derived photoreceptor precursors restores retinal structure and function in degenerative mice.
        PLoS One. 2011; 6: e18992
        • Lu B.
        • Malcuit C.
        • Wang S.
        • et al.
        Long-term safety and function of RPE from human embryonic stem cells in preclinical models of macular degeneration.
        Stem Cells. 2009; 27: 2126-2135
        • Marmorstein A.D.
        • Finnemann S.C.
        • Bonilha V.L.
        • Rodriguez-Boulan E.
        Morphogenesis of the retinal pigment epithelium: toward understanding retinal degenerative diseases.
        Ann N Y Acad Sci. 1998; 857: 1-12
        • Eisenfeld A.
        • Bunt-Milam A.
        • Saari J.
        Immunocytochemical localization of interphotoreceptor retinoid-binding protein in developing normal and RCS rat retinas.
        Invest Ophthalmol Vis Sci. 1985; 26: 775-778