Photoreceptor Precursors Derived from Three-dimensional Embryonic Stem Cell Cultures Integrate and Mature Within Adult Degenerate Retina

Overview

Journal Nat Biotechnol

Specialty Biotechnology

Date 2013 Jul 23

PMID 23873086

Citations 195

Authors

Anai Gonzalez-Cordero

Emma L West

Rachael A Pearson

Yanai Duran

Livia S Carvalho

Colin J Chu

Arifa Naeem

Samuel J I Blackford

Anastasios Georgiadis

Jorn Lakowski

Mike Hubank

Alexander J Smith

James W B Bainbridge

Jane C Sowden

Robin R Ali

Affiliations

Soon will be listed here.

Abstract

Irreversible blindness caused by loss of photoreceptors may be amenable to cell therapy. We previously demonstrated retinal repair and restoration of vision through transplantation of photoreceptor precursors obtained from postnatal retinas into visually impaired adult mice. Considerable progress has been made in differentiating embryonic stem cells (ESCs) in vitro toward photoreceptor lineages. However, the capability of ESC-derived photoreceptors to integrate after transplantation has not been demonstrated unequivocally. Here, to isolate photoreceptor precursors fit for transplantation, we adapted a recently reported three-dimensional (3D) differentiation protocol that generates neuroretina from mouse ESCs. We show that rod precursors derived by this protocol and selected via a GFP reporter under the control of a Rhodopsin promoter integrate within degenerate retinas of adult mice and mature into outer segment-bearing photoreceptors. Notably, ESC-derived precursors at a developmental stage similar to postnatal days 4-8 integrate more efficiently compared with cells at other stages. This study shows conclusively that ESCs can provide a source of photoreceptors for retinal cell transplantation.

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References

Eberle D, Schubert S, Postel K, Corbeil D, Ader M . Increased integration of transplanted CD73-positive photoreceptor precursors into adult mouse retina. Invest Ophthalmol Vis Sci. 2011; 52(9):6462-71. DOI: 10.1167/iovs.11-7399. View

Tucker B, Park I, Qi S, Klassen H, Jiang C, Yao J . Transplantation of adult mouse iPS cell-derived photoreceptor precursors restores retinal structure and function in degenerative mice. PLoS One. 2011; 6(4):e18992. PMC: 3084746. DOI: 10.1371/journal.pone.0018992. View

Blackshaw S, Harpavat S, Trimarchi J, Cai L, Huang H, Kuo W . Genomic analysis of mouse retinal development. PLoS Biol. 2004; 2(9):E247. PMC: 439783. DOI: 10.1371/journal.pbio.0020247. View

West E, Pearson R, Tschernutter M, Sowden J, MacLaren R, Ali R . Pharmacological disruption of the outer limiting membrane leads to increased retinal integration of transplanted photoreceptor precursors. Exp Eye Res. 2008; 86(4):601-11. PMC: 2394572. DOI: 10.1016/j.exer.2008.01.004. View

Bartsch U, Oriyakhel W, Kenna P, Linke S, Richard G, Petrowitz B . Retinal cells integrate into the outer nuclear layer and differentiate into mature photoreceptors after subretinal transplantation into adult mice. Exp Eye Res. 2008; 86(4):691-700. DOI: 10.1016/j.exer.2008.01.018. View

Singh M, Charbel Issa P, Butler R, Martin C, Lipinski D, Sekaran S . Reversal of end-stage retinal degeneration and restoration of visual function by photoreceptor transplantation. Proc Natl Acad Sci U S A. 2013; 110(3):1101-6. PMC: 3549087. DOI: 10.1073/pnas.1119416110. View

Chen S, Wang Q, Nie Z, Sun H, Lennon G, Copeland N . Crx, a novel Otx-like paired-homeodomain protein, binds to and transactivates photoreceptor cell-specific genes. Neuron. 1997; 19(5):1017-30. DOI: 10.1016/s0896-6273(00)80394-3. View

Osakada F, Ikeda H, Sasai Y, Takahashi M . Stepwise differentiation of pluripotent stem cells into retinal cells. Nat Protoc. 2009; 4(6):811-24. DOI: 10.1038/nprot.2009.51. View

Hirami Y, Osakada F, Takahashi K, Okita K, Yamanaka S, Ikeda H . Generation of retinal cells from mouse and human induced pluripotent stem cells. Neurosci Lett. 2009; 458(3):126-31. DOI: 10.1016/j.neulet.2009.04.035. View

10.

Meyer J, Shearer R, Capowski E, Wright L, Wallace K, McMillan E . Modeling early retinal development with human embryonic and induced pluripotent stem cells. Proc Natl Acad Sci U S A. 2009; 106(39):16698-703. PMC: 2757802. DOI: 10.1073/pnas.0905245106. View

11.

Phillips M, Wallace K, Dickerson S, Miller M, Verhoeven A, Martin J . Blood-derived human iPS cells generate optic vesicle-like structures with the capacity to form retinal laminae and develop synapses. Invest Ophthalmol Vis Sci. 2012; 53(4):2007-19. PMC: 3648343. DOI: 10.1167/iovs.11-9313. View

12.

Davidoff A, Ng C, Sleep S, Gray J, Azam S, Zhao Y . Purification of recombinant adeno-associated virus type 8 vectors by ion exchange chromatography generates clinical grade vector stock. J Virol Methods. 2004; 121(2):209-15. DOI: 10.1016/j.jviromet.2004.07.001. View

13.

Ali R, Sowden J . Regenerative medicine: DIY eye. Nature. 2011; 472(7341):42-3. DOI: 10.1038/472042a. View

14.

Osakada F, Ikeda H, Mandai M, Wataya T, Watanabe K, Yoshimura N . Toward the generation of rod and cone photoreceptors from mouse, monkey and human embryonic stem cells. Nat Biotechnol. 2008; 26(2):215-24. DOI: 10.1038/nbt1384. View

15.

Lakowski J, Han Y, Pearson R, Gonzalez-Cordero A, West E, Gualdoni S . Effective transplantation of photoreceptor precursor cells selected via cell surface antigen expression. Stem Cells. 2011; 29(9):1391-404. PMC: 3303132. DOI: 10.1002/stem.694. View

16.

Lamba D, Gust J, Reh T . Transplantation of human embryonic stem cell-derived photoreceptors restores some visual function in Crx-deficient mice. Cell Stem Cell. 2009; 4(1):73-9. PMC: 2713676. DOI: 10.1016/j.stem.2008.10.015. View

17.

Pearson R, Barber A, West E, MacLaren R, Duran Y, Bainbridge J . Targeted disruption of outer limiting membrane junctional proteins (Crb1 and ZO-1) increases integration of transplanted photoreceptor precursors into the adult wild-type and degenerating retina. Cell Transplant. 2010; 19(4):487-503. PMC: 2938729. DOI: 10.3727/096368909X486057. View

18.

Nakano T, Ando S, Takata N, Kawada M, Muguruma K, Sekiguchi K . Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell. 2012; 10(6):771-785. DOI: 10.1016/j.stem.2012.05.009. View

19.

Furukawa T, Morrow E, Cepko C . Crx, a novel otx-like homeobox gene, shows photoreceptor-specific expression and regulates photoreceptor differentiation. Cell. 1997; 91(4):531-41. DOI: 10.1016/s0092-8674(00)80439-0. View

20.

Koulen P, Brandstatter J . Pre- and Postsynaptic Sites of Action of mGluR8a in the mammalian retina. Invest Ophthalmol Vis Sci. 2002; 43(6):1933-40. View