Swine Cone and Rod Precursors Arise Sequentially and Display Sequential and Transient Integration and Differentiation Potential Following Transplantation

Wang, Wei; Zhou, Liang; Lee, Sang Joon; Liu, Yongqing; Castro, Juan Fernandez de; Emery, Douglas; Vukmanic, Eric; Kaplan, Henry J.; Dean, Douglas C.

doi:10.1167/iovs.13-12600

Cited by 18 publications

(27 citation statements)

References 19 publications

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“…In the pig, the outer two rows of the ONL are comprised only of cones (Fig. 2A; Wang et al 2014). Although cone OS were similar in P23H and WT litter mates prior to birth (Fig.…”

Section: Resultsmentioning

confidence: 99%

Two-Step Reactivation of Dormant Cones in Retinitis Pigmentosa

et al. 2016

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Most Retinitis Pigmentosa (RP) mutations arise in rod photoreceptor genes, leading to diminished peripheral and nightime vision. Using a pig model of autosomal-dominant RP, we show glucose becomes sequestered in the retinal pigment epithelium (RPE), and thus is not transported to photoreceptors. The resulting starvation for glucose metabolites impairs synthesis of cone visual pigment -rich outer segments (OS), and then their mitochondrial-rich inner segments dissociate. Loss of these functional structures diminishes cone-dependent high-resolution central vision, which is utilized for most daily tasks. By transplanting wild-type rods, to restore glucose transport, or directly replacing glucose in the subretinal space, to bypass its retention in the RPE, we can regenerate cone functional structures, reactivating the dormant cells. Beyond providing metabolic building blocks for cone functional structures, we show glucose induces thioredoxin-interacting protein (Txnip) to regulate Akt signaling, thereby shunting metabolites toward aerobic glucose metabolism and regenerating cone OS synthesis.

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“…In the pig, the outer two rows of the ONL are comprised only of cones (Fig. 2A; Wang et al 2014). Although cone OS were similar in P23H and WT litter mates prior to birth (Fig.…”

Section: Resultsmentioning

confidence: 99%

Two-Step Reactivation of Dormant Cones in Retinitis Pigmentosa

et al. 2016

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“…Despite these advances, the majority of studies focusing on photoreceptor replacement therapies were performed in rodents using rods. Recently, Wang et al [65] transplanted dissociated retinal tissue isolated from the pig eye at different developmental stages into the adult pig retina. Depending on the age of the donor cells, they observed the generation of more cones when isolated at earlier stages (at E50 or E57) or rod photoreceptors when isolated at later stages (at E65) within the recipient retina [65], in line with previous studies in mice [41 •• ].…”

Section: Transplantation Of Cone Photoreceptorsmentioning

confidence: 99%

“…Recently, Wang et al [65] transplanted dissociated retinal tissue isolated from the pig eye at different developmental stages into the adult pig retina. Depending on the age of the donor cells, they observed the generation of more cones when isolated at earlier stages (at E50 or E57) or rod photoreceptors when isolated at later stages (at E65) within the recipient retina [65], in line with previous studies in mice [41 •• ]. However, the lack of an abundant source and enrichment methods for cone photoreceptors currently limits the investigation of cone photoreceptor transplantation for the restoration of cone-mediated visual function.…”

Section: Transplantation Of Cone Photoreceptorsmentioning

confidence: 99%

Photoreceptor transplantation into the mammalian retina

Santos-Ferreira

Postel

Ader

2014

Curr Ophthalmol Rep

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Loss of the light-sensing photoreceptors results in vision impairment and blindness, representing one of the main causes for disability in industrialized societies. Although the pathophysiology of diseases such as agerelated macular degeneration, retinitis pigmentosa, or conerod dystrophies is highly heterogeneous, the final endpoint of such conditions is the degeneration of photoreceptors with no established therapies currently available for their replacement. However, recent preclinical studies demonstrated the feasibility of cell transplantation into the adult mammalian retina. Indeed, young post-mitotic photoreceptors represent a suitable cell type for such replacement approach as they showed proper integration and maturation following grafting. Importantly, donor photoreceptors connected to endogenous neurons allowing some functional rescue in mouse models of night blindness. Furthermore, methods for the generation of transplantable photoreceptors from pluripotent stem cells in vitro have been established. Here, we will review recent developments in the field of photoreceptor transplantation and will discuss still existing roadblocks toward clinical application.

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“…Cyclosporine treatment does not improve the longterm survival in a rabbit model. 11 We have shown that pRPC allotransplants are well tolerated in wild-type 12 and retinal degenerative pigs, 13 while other groups have demonstrated this for freshly isolated 4 and iPSc-derived 14 photoreceptor precursors. The most important information comes from clinical observations 15 showing that without immunosuppression the rejection rate remains high, possibly due to major histocompatibility complex (MHC) II expression.…”

Section: Introductionmentioning

confidence: 96%

“…Previously we and others have shown that retinal progenitor cells/ photoreceptor precursors integrate into the host retina and differentiate into mature photoreceptors after transplantation into the subretinal space. [1][2][3][4] While there are no current clinical studies on photoreceptor replacement, retinal pigment epithelium cells 5 and neural progenitor cells 6 have recently been transplanted to patients as allografts with a comprehensive immunosuppressive regimen.…”

Section: Introductionmentioning

confidence: 99%

The Effect of Transient Local Anti-inflammatory Treatment on the Survival of Pig Retinal Progenitor Cell Allotransplants

Abud

Baranov

Hicks

et al. 2015

Trans. Vis. Sci. Tech.

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Purpose: The development of photoreceptor replacement therapy for retinal degenerative disorders requires the identification of the optimal cell source and immunosuppressive regimen in a large animal model. Allotransplants are not acutely rejected in swine subretinal space, although it is not known if survival can be improved with immunosuppression. Here we investigated the survival and integration of expanded pig retinal progenitor cells (pRPCs) in normal recipients with and without transient anti-inflammatory suppression.Methods: pRPCs were derived from the neural retina of E60 GFP transgenic pigs, expanded for six passages, characterized, and transplanted into the subretinal space of 12 pigs. Six recipients received a single intravitreal injection of rapamycin and dexamethasone.Results: pRPCs expressed the photoreceptor development genes Sox2, Pax6, Lhx2, Crx, Nrl, and Recoverin in vitro. Transplanted cells were identified in 9 out of 12 recipients 4 weeks after the injection. pRPCs integrated primarily into the photoreceptor inner segment layer and outer nuclear layer with single cells present in the inner nuclear layer. Donor cells remained recoverin-positive and acquired rhodopsin. We did not observe any signs of graft proliferation. The immunosuppression did not affect the survival or distribution of grafts. No macrophage infiltration or loss of retinal structure was observed in either group.Conclusions: Local immunosuppression with rapamycin and dexamethasone does not improve the outcome of pRPC allotransplantation into the subretinal space.Translational Relevance: Survival and integration of pRPC together with the lack of graft proliferation suggests that allogeneic RPC transplantation without transient immunosuppression is a favorable approach for photoreceptor cell replacement.

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Swine Cone and Rod Precursors Arise Sequentially and Display Sequential and Transient Integration and Differentiation Potential Following Transplantation

Abstract: Consistent with their sequential appearances in embryonic retina, these results demonstrate sequential and surprisingly narrow developmental windows for integration/differentiation of cone and rod precursors following transplantation.

Cited by 18 publications

References 19 publications

Two-Step Reactivation of Dormant Cones in Retinitis Pigmentosa

Two-Step Reactivation of Dormant Cones in Retinitis Pigmentosa

Photoreceptor transplantation into the mammalian retina

The Effect of Transient Local Anti-inflammatory Treatment on the Survival of Pig Retinal Progenitor Cell Allotransplants

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