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Stem Cells Dev. 2019 Jun 18. doi: 10.1089/scd.2019.0090. [Epub ahead of print]

Transplantation of human embryonic stem cell derived retinal tissue in the subretinal space of the cat eye.

Author information

1
BioTime Inc, 17512, Alameda, California, United States ; rsingh@biotimeinc.com.
2
Michigan State University, 3078, Dept. of Small Animal Clinical Sciences, East Lansing, Michigan, United States ; occelli@cvm.msu.edu.
3
BioTime Inc, 17512, Alameda, California, United States ; Fbinette@biotimeinc.com.
4
Michigan State University, 3078, Dept. of Small Animal Clinical Sciences, East Lansing, Michigan, United States ; peter315@msu.edu.
5
BioTime Inc, 17512, Alameda, California, United States , 94502-2215 ; inasonkin@biotimeinc.com.

Abstract

To develop biological approaches to restore vision, we developed a method of transplanting stem cell-derived retinal tissue into the subretinal space of a large eye animal model (cat). Human embryonic stem cells (hESC) were differentiated to retinal organoids in a dish. HESC-derived retinal tissue was introduced into the subretinal space of wild-type cats following a pars plana vitrectomy. The cats were systemically immunosuppressed with either prednisolone or prednisolone plus cyclosporine A. The eyes were examined by fundoscopy and spectral domain-optical coherence tomography (SD-OCT) imaging for adverse effects due to the presence of the subretinal grafts. Immunohistochemistry was done with antibodies to retinal and human markers to delineate graft survival, differentiation and integration into cat retina. We successfully delivered hESC-derived retinal tissue into the subretinal space of the cat eye. We observed strong infiltration of immune cells in the graft and surrounding tissue in the cats treated with prednisolone. In contrast we showed better survival and low immune response to the graft in cats treated with prednisolone plus cyclosporine A. Immunohistochemistry with antibodies (STEM121, CALB2, DCX and SMI-312) revealed large number of graft-derived fibers connecting the graft and the host. We also show presence of human specific synaptophysin puncta in the cat retina. This work demonstrates feasibility of engrafting human embryonic stem cells derived retinal tissue into the subretinal space of large eye animal models. Transplanting retinal tissue in degenerating cat retina will enable rapid development of preclinical in vivo work focused on vision restoration.

PMID:
31210100
DOI:
10.1089/scd.2019.0090

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