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Imaging Transplanted Photoreceptors in Living Nonhuman Primates with Single-Cell Resolution

Abstract

Stem cell-based transplantation therapies offer hope for currently untreatable retinal degenerations; however, preclinical progress has been largely confined to rodent models. Here, we describe an experimental platform for accelerating photoreceptor replacement therapy in the nonhuman primate, which has a visual system much more similar to the human. We deployed fluorescence adaptive optics scanning light ophthalmoscopy (FAOSLO) to noninvasively track transplanted photoreceptor precursors over time at cellular resolution in the living macaque. Fluorescently labeled photoreceptors generated from a CRX human embryonic stem cell (hESC) reporter line were delivered subretinally to macaques with normal retinas and following selective ablation of host photoreceptors using an ultrafast laser. The fluorescent reporter together with FAOSLO allowed transplanted photoreceptor precursor survival, migration, and neurite formation to be monitored over time in vivo. Histological examination suggested migration of photoreceptor precursors to the outer plexiform layer and potential synapse formation in ablated areas in the macaque eye.

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References
1.
Phillips M, Jiang P, Howden S, Barney P, Min J, York N . A Novel Approach to Single Cell RNA-Sequence Analysis Facilitates In Silico Gene Reporting of Human Pluripotent Stem Cell-Derived Retinal Cell Types. Stem Cells. 2017; 36(3):313-324. PMC: 5823737. DOI: 10.1002/stem.2755. View

2.
Moshiri A, Chen R, Kim S, Harris R, Li Y, Raveendran M . A nonhuman primate model of inherited retinal disease. J Clin Invest. 2019; 129(2):863-874. PMC: 6355306. DOI: 10.1172/JCI123980. View

3.
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

4.
Phillips M, Perez E, Martin J, Reshel S, Wallace K, Capowski E . Modeling human retinal development with patient-specific induced pluripotent stem cells reveals multiple roles for visual system homeobox 2. Stem Cells. 2014; 32(6):1480-92. PMC: 4037340. DOI: 10.1002/stem.1667. View

5.
Sharma R, Schwarz C, Williams D, Palczewska G, Palczewski K, Hunter J . In Vivo Two-Photon Fluorescence Kinetics of Primate Rods and Cones. Invest Ophthalmol Vis Sci. 2016; 57(2):647-57. PMC: 4771186. DOI: 10.1167/iovs.15-17946. View