Sheets of human retinal progenitor transplants improve vision in rats with severe retinal degeneration

Abstract

Loss of photoreceptors and other retinal cells is a common endpoint in retinal degenerate (RD) diseases that cause blindness. Retinal transplantation is a potential therapy to replace damaged retinal cells and improve vision. In this study, we examined the development of human fetal retinal sheets with or without their retinal pigment epithelium (RPE) transplanted to immunodeficient retinal degenerate rho S334ter-3 rats. Sheets were dissected from fetal human eyes (11-15.7 weeks gestation) and then transplanted to the subretinal space of 24-31 d old RD nude rats. Every month post surgery, eyes were imaged by high-resolution spectral-domain optical coherence tomography (SD-OCT). SD-OCT showed that transplants were placed into the subretinal space and developed laminated areas or rosettes, with clear development of plexiform layers first seen in OCT at 3 months post surgery. Several months later, as could be expected by the much slower development of human cells compared to rat cells, transplant photoreceptors developed inner and later outer segments. Retinal sections were analyzed by immunohistochemistry for human and retinal markers and confirmed the formation of several retinal subtypes within the retinal layers. Transplant cells extended processes and a lot of the cells could also be seen migrating into the host retina. At 5.8-8.6 months post surgery, selected rats were exposed to light flashes and recorded for visual responses in superior colliculus, (visual center in midbrain). Four of seven rats with transplants showed responses to flashes of light in a limited area of superior colliculus. No response with the same dim light intensity was found in age-matched RD controls (non-surgery or sham surgery). In summary, our data showed that human fetal retinal sheets transplanted to the severely disturbed subretinal space of RD nude rats develop mature photoreceptors and other retinal cells, integrate with the host and induce vision improvement.

Transplantation of Human Embryonic Stem Cell-Derived Retinal Tissue in the Subretinal Space of the Cat Eye

“…Technologies such as retinal prosthetic devices [139][140][141][142] and fetal retina transplantation [15,18,19,[38][39][40]57,143,144] indicate that introducing new functional light-capturing sensors (photosensitive diodes in case of neuroprosthetic devices and photoreceptors in case of fetal retina grafts) is an appropriate way forward in treating RD. However, both of these technologies have limitations.…”

“…Derivation of retinal tissue in a dish from human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs) creates new opportunities for designing tissue replacement therapies for blindness and addresses the need to preserve retinal architecture to restore vision. Moreover, this approach can utilize the 30-year experience and knowledge of transplanting sheets of human fetal retina [13,57]. It is also realistic as it is already revealing signs of clinical promise in animal models.…”

Development of a protocol for maintaining viability while shipping organoid‐derived retinal tissue

“…Developing preclinical vision restoration protocols based on transplanting stem cell–derived retinal tissue (Lin et al, ; Singh et al, ) or cells (Hambright et al, ) into the ocular space (subretinal or epiretinal) of experimental animals requires close coordination of work between the team generating the organoids and the team doing surgical grafting. Precise and reliable methods are needed, because (a) biological material is expensive and takes time to generate, (b) the surgical team, equipment, and surgical rooms are scheduled in advance and availability of all three takes time to plan, and (c) critically, the animals, especially those models with progressive retinal atrophy (Petersen‐Jones & Komaromy, ; Seiler et al, ), are scheduled for surgeries on specific days depending on the dynamics of retina degeneration and multiple experiments are usually done before each study is completed (with each cohort of animals being implanted at the same age, to be able to pool the data from multiple experiments).…”

“…Developing preclinical vision restoration protocols based on transplanting stem cell-derived retinal tissue (Lin et al, 2018;Singh et al, 2019) or cells (Hambright et al, 2012) are scheduled for surgeries on specific days depending on the dynamics of retina degeneration and multiple experiments are usually done before each study is completed (with each cohort of animals being implanted at the same age, to be able to pool the data from multiple experiments). Developing neural retinal tissue is sensitive to shipping conditions and needs to be transported quickly and in the optimal conditions to maintain viability ahead of transplantation.…”

Structural engraftment and topographic spacing of transplanted human stem cell-derived retinal ganglion cells

“…Retinal ganglion cell (RGC) replacement provides a possible therapeutic strategy to reverse vision loss from optic neuropathies such as glaucoma, the world's leading cause of irreversible blindness. 1,2 Promising photoreceptor transplantation studies [3][4][5][6] (including human-rodent xenografts [7][8][9][10][11] ) provide proof of principle that vision restoration may be attainable by mammalian retinal cell replacement. However, unlike photoreceptors, RGCs are projection neurons and their functional replacement requires bidirectional visual pathway integration.…”