Systemic immunosuppression promotes survival and integration of subretinally implanted human ESC-derived photoreceptor precursors in dogs

Dolgova, Natalia V.; Phillips, M. Joseph; Savina, Svetlana; Ludwig, Allison L.; Stuedemann, Sara; Nlebedum, UC; Wolfe, John H.; Garden, Oliver A.; Maminishkis, Arvydas; Amaral, Juan; Bharti, Kapil; Gamm, David M.; Aguirre, Gustavo D.; Ripolles-García, Ana

doi:10.1016/j.stemcr.2022.06.009

Cited by 21 publications

(24 citation statements)

References 37 publications

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“…This might also provide insight if donor cells invade the host, or if host cells, like MG, might actively extend processes and take up donor cells. As another example, the subretinal region in the eye is immune privileged, but transplant rejection requiring immune suppression is a limiting factor in animals (14,(59)(60)(61). Studies in the HRO system might advance our understanding about the donor-host compatibility in a human setting.…”

Section: Discussionmentioning

confidence: 99%

“…However, even though HROs are a reduced system, these might even more closely reproduce a healthy in vivo setting ex vivo compared to culture of primary retina, which spontaneously degenerate ex vivo (43,62). With the availability of organoids from different organisms (63,64), comparison of other species-specific differences might become possible, for example, to determine large animal models optimal for in vivo studies, which might be useful to optimize surgical methods for clinical translation (65)(66)(67). Further, the herein established HRO transplantation assay might advance several remaining major questions in cell replacement therapy development towards clinical translation.…”

Section: Discussionmentioning

confidence: 99%

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Human photoreceptor cell transplants integrate into human retina organoids

Wagner

Carrera

Kurth

et al. 2022

Preprint

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Cell transplantation is a promising therapeutic approach to recover loss of neurons and vision in patient retinas. So far, human photoreceptor transplants restored some visual function in degenerating mouse retina. Whether retinal cell transplants also integrate into human retina, and how to optimize this for different pathologies are still unknown. Here, we sought to determine if human retina organoids generated from pluripotent stem cells might assist cell replacement therapy development in a human-to-human setting. Models for intra- and subretinal cell transplantation strategies were explored: Photoreceptor donor cells carrying a transgenic fluorescent reporter were enriched from acutely dissociated human retinal organoids. Donor cells were precisely transplanted by microinjection into the retina of host organoids, but high cell numbers might require multiple injections posing potential damage. Alternatively, donor cells were transplanted in large numbers by placing them in subretinal-like contact to the apical organoid surface. Using postmitotic retinal organoids (age >170-days) as a source for donor cells and as hosts, we show that six weeks after subretinal-like transplantation, large clusters of photoreceptors reproducibly incorporate into the host retina. Transplanted clusters frequently are located within or across the host photoreceptor layer, include cone and rod photoreceptors, and become infiltrated by cell processes of host Müller glia, indicative of structural integration. Histological and ultrastructural data of virally-labeled photoreceptor transplants show characteristic morphological and structural features of polarized photoreceptors: inner segments and ribbon synapses, and donor-host cell contacts develop contributing to the retinal outer limiting membrane. These results demonstrate that human retinal organoids provide a preclinical research system for cell replacement therapies.Graphical abstract

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Human photoreceptor cell transplants integrate into human retina organoids

Wagner

Carrera

Kurth

et al. 2022

Preprint

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“…Notably, these generated photoreceptors have synaptic pedicle-like structures which could establish contact with second-order neurons. Thus, their findings set the stage for evaluating functional vision restoration following photoreceptor replacement in canine models of inherited retinal degeneration [ 40 ].…”

Section: Strategies For Treating the Retinal Diseases With Mesenchyma...mentioning

confidence: 99%

Mesenchymal-Stem-Cell-Based Strategies for Retinal Diseases

Chen

Jiang

Duan

et al. 2022

Genes

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Retinal diseases are major causes of irreversible vision loss and blindness. Despite extensive research into their pathophysiology and etiology, pharmacotherapy effectiveness and surgical outcomes remain poor. Based largely on numerous preclinical studies, administration of mesenchymal stem cells (MSCs) as a therapeutic strategy for retinal diseases holds great promise, and various approaches have been applied to the therapies. However, hindered by the retinal barriers, the initial vision for the stem cell replacement strategy fails to achieve the anticipated effect and has now been questioned. Accumulating evidence now suggests that the paracrine effect may play a dominant role in MSC-based treatment, and MSC-derived extracellular vesicles emerge as a novel compelling alternative for cell-free therapy. This review summarizes the therapeutic potential and current strategies of this fascinating class of cells in retinal degeneration and other retinal dysfunctions.

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“…Visual function (behavioral test) was modestly improved at 1.5 year in one monkey in the grafted laser-lesioned area compared to control retinal area, but no improvement was recorded by focal ERG. A recent study in dogs reported that retinal sheets obtained from D104-151 organoids survived up to 3-5 months in the subretinal space of normal dogs and can extend axons beyond the outer limiting membrane when transplanted in dogs with retinal degeneration (rcd1/PDE6B mutations) (Ripolles-Garcia et al 2022).…”

Section: Tissue Formulationmentioning

confidence: 99%

Photoreceptor Cell Replacement Using Pluripotent Stem Cells: Current Knowledge and Remaining Questions

Monville

Goureau

M’Barek

2022

Cold Spring Harb Perspect Med

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Retinal degeneration is an increasing global burden without cure for the majority of patients. Once retinal cells have degenerated, vision is permanently lost. Different strategies have been developed in the recent years to prevent retinal degeneration or to restore sight (e.g., gene therapy, cell therapy and electronic implants). Herein, we present current treatment strategies with a focus on cell therapy for photoreceptor replacement using human pluripotent stem cells. We will describe the state of the art and discuss obstacles and limitations observed in preclinical animal models as well as future directions to improve graft integration and functionality.

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Systemic immunosuppression promotes survival and integration of subretinally implanted human ESC-derived photoreceptor precursors in dogs

Cited by 21 publications

References 37 publications

Human photoreceptor cell transplants integrate into human retina organoids

Human photoreceptor cell transplants integrate into human retina organoids

Mesenchymal-Stem-Cell-Based Strategies for Retinal Diseases

Photoreceptor Cell Replacement Using Pluripotent Stem Cells: Current Knowledge and Remaining Questions

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