Evidence for endogenous exchange of cytoplasmic material between a subset of cone and rod photoreceptors within the adult mammalian retina via direct cell-cell connections

Heisterkamp, Patrick; Borsch, Oliver; Lezama, Nundehui Diaz; Gasparini, Sylvia J.; Fathima, Adeeba; Carvalho, Lívia S.; Wagner, Felix; Karl, Mike O.; Schlierf, Michael; Ader, Marius

doi:10.1016/j.exer.2022.109033

Cited by 14 publications

(10 citation statements)

References 28 publications

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“…Recent studies in mice in vivo showed that human PRs incorporate in large cell clusters when transplanted into the subretinal space (14), whereas mouse PRs rarely integrate (11–13, 17). To determine whether human PRs incorporate upon subretinal-like conditions into healthy control host HROs (Fig.2A), sections of experimental HROs were analyzed 6 weeks after transplantation by histology and immunohistochemistry.…”

Section: Resultsmentioning

confidence: 99%

“…Previous animal studies showed that material transfer of fluorescent reporter from mouse (11–13, 17) but not human (14) PR transplants to host PRs may be misinterpreted as integrated PR transplants. We used a dual reporter approach to assess this: CRX-mCHERRY+ human PRs served as donors, HRO hosts were derived from hiPSCs that ubiquitously express transgenic nuclear enhanced GFP in all cells (NLS-eGFP) (Fig.3A, B), so that eGFP and mCHERRY double-positive nuclei would indicate material transfer.…”

Section: Resultsmentioning

confidence: 99%

“…Whereas mouse photoreceptors integrate in smaller numbers, if at all, into the host retina (11)(12)(13), human photoreceptors, particularly cones, have recently been shown to structurally integrate in large clusters and/or contact host second-order neurons and Müller glia (14,15). While exchange of genetic and protein material has been shown to frequently occur in mouse-to-mouse photoreceptor transplants (11)(12)(13)(16)(17)(18), this phenomenon was not observed in human transplants into rodent models (14,(19)(20)(21). Hence, animal studies support the possibility of beneficial cell replacement therapy, posing the questions how to effectively translate findings to the clinic, and which patients at what stage of pathology would profit most.…”

Section: Introductionmentioning

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: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human photoreceptor cell transplants integrate into human retina organoids

Wagner

Carrera

Kurth

et al. 2022

Preprint

Self Cite

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“…It was thought that material exchange required PR-to-PR communication, which could not occur in severe RD when the PR layer is completely gone 134,137. Cytoplasmic transfer between PRs also occurs during normal retinal development 138. However, transfer can also be seen from PRs to the Muller cells and ACs in the inner nuclear layer when grafting cells to rats with normal outer nuclear layer 103.…”

Section: Post-transplantation Analysismentioning

confidence: 99%

“…134,137 Cytoplasmic transfer between PRs also occurs during normal retinal development. 138 However, transfer can also be seen from PRs to the Muller cells and ACs in the inner nuclear layer when grafting cells to rats with normal outer nuclear layer. 103 Thus, the identity of donor cells in the host retina needs to be clearly demonstrated by nuclear labels (eg, male donor into female host, 37,103,105,132 or a human nuclear marker for hPSC-derived transplants in rodent hosts 16,19,43 ).…”

Section: Cytoplasmic Materials Transfer Between Transplant and Hostmentioning

confidence: 99%

The Prospects for Retinal Organoids in Treatment of Retinal Diseases

Xue

Lin

Chen

et al. 2022

Asia-Pacific Journal of Ophthalmology

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Retinal degeneration (RD) is a significant cause of incurable blindness worldwide. Photoreceptors and retinal pigmented epithelium are irreversibly damaged in advanced RD. Functional replacement of photoreceptors and/or retinal pigmented epithelium cells is a promising approach to restoring vision. This paper reviews the current status and explores future prospects of the transplantation therapy provided by pluripotent stem cell-derived retinal organoids (ROs). This review summarizes the status of rodent RD disease models and discusses RO culture and analytical tools to evaluate RO quality and function. Finally, we review and discuss the studies in which ROderived cells or sheets were transplanted. In conclusion, methods to derive ROs from pluripotent stem cells have significantly improved and become more efficient in recent years. Meanwhile, more novel technologies are applied to characterize and validate RO quality. However, opportunity remains to optimize tissue differentiation protocols and achieve better RO reproducibility. In order to screen high-quality ROs for downstream applications, approaches such as noninvasive and label-free imaging and electrophysiological functional testing are promising and worth further investigation. Lastly, transplanted RO-derived tissues have allowed improvements in visual function in several RD models, showing promises for clinical applications in the future.

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Recombinant protein delivery enables modulation of the phototransduction cascade in mouse retina

Asteriti,

Marino,

Avesani

et al. 2023

Cell. Mol. Life Sci.

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Inherited retinal dystrophies are often associated with mutations in the genes involved in the phototransduction cascade in photoreceptors, a paradigmatic signaling pathway mediated by G protein-coupled receptors. Photoreceptor viability is strictly dependent on the levels of the second messengers cGMP and Ca2+. Here we explored the possibility of modulating the phototransduction cascade in mouse rods using direct or liposome-mediated administration of a recombinant protein crucial for regulating the interplay of the second messengers in photoreceptor outer segments. The effects of administration of the free and liposome-encapsulated human guanylate cyclase-activating protein 1 (GCAP1) were compared in biological systems of increasing complexity (in cyto, ex vivo, and in vivo). The analysis of protein biodistribution and the direct measurement of functional alteration in rod photoresponses show that the exogenous GCAP1 protein is fully incorporated into the mouse retina and photoreceptor outer segments. Furthermore, only in the presence of a point mutation associated with cone-rod dystrophy in humans p.(E111V), protein delivery induces a disease-like electrophysiological phenotype, consistent with constitutive activation of the retinal guanylate cyclase. Our study demonstrates that both direct and liposome-mediated protein delivery are powerful complementary tools for targeting signaling cascades in neuronal cells, which could be particularly important for the treatment of autosomal dominant genetic diseases.

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Evidence for endogenous exchange of cytoplasmic material between a subset of cone and rod photoreceptors within the adult mammalian retina via direct cell-cell connections

Cited by 14 publications

References 28 publications

Human photoreceptor cell transplants integrate into human retina organoids

Human photoreceptor cell transplants integrate into human retina organoids

The Prospects for Retinal Organoids in Treatment of Retinal Diseases

Recombinant protein delivery enables modulation of the phototransduction cascade in mouse retina

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