Mechanisms Underlying the Visual Benefit of Cell Transplantation for the Treatment of Retinal Degenerations

Léveillard, Thierry; Klipfel, Laurence

doi:10.3390/ijms20030557

Cited by 8 publications

(6 citation statements)

References 111 publications

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“…The discovery of biomaterial transfer as a potential false indicator for integration in previous mouse studies of photoreceptor transplantation ( 45 , 69 – 73 ) underscores the need to investigate the mechanistic underpinnings of neuroretinal cell therapies ( 6 , 7 , 44 , 74 , 78 , 79 ). The synaptic tracing tools and assay methods employed herein provide a rigorous and unbiased means of assessing biomaterial transfer and other confounding variables.…”

Section: Discussionmentioning

confidence: 99%

“…Despite xenograft limitations, modest alterations to light-evoked responses have been reported after transplantation of hPSC-RO-derived photoreceptors as single cells ( 5 , 13 , 15 , 41 , 42 ) or sectioned tissue sheets ( 18 , 21 , 43 ) in different animal model systems ( 5 , 42 ). However, it can be difficult to determine whether such function is attributable to cell replacement with synaptic reconstruction or to indirect effects on host neurons via neuroprotective factors or biomaterial transfer ( 6 , 19 , 44 , 45 ). Furthermore, nearly all electrophysiologic and behavioral tests that assess the outcomes of retinal neuron replacement in preclinical animal models rely on the assumption that synaptic connections with donor cells have occurred ( 5 , 13 , 15 , 18 , 20 , 21 , 41 – 43 ).…”

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confidence: 99%

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Re-formation of synaptic connectivity in dissociated human stem cell-derived retinal organoid cultures

Ludwig

Mayerl

Gao

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Human pluripotent stem cell (hPSC)-derived retinal organoids (ROs) can efficiently and reproducibly generate retinal neurons that have potential for use in cell replacement strategies [Capowski et al. , Development 146, dev171686 (2019)]. The ability of these lab-grown retinal neurons to form new synaptic connections after dissociation from ROs is key to building confidence in their capacity to restore visual function. However, direct evidence of reestablishment of retinal neuron connectivity via synaptic tracing has not been reported to date. The present study employs an in vitro, rabies virus-based, monosynaptic retrograde tracing assay [Wickersham et al., Neuron 53, 639–647 (2007); Sun et al., Mol. Neurodegener. 14, 8 (2019)] to identify de novo synaptic connections among early retinal cell types following RO dissociation. A reproducible, high-throughput approach for labeling and quantifying traced retinal cell types was developed. Photoreceptors and retinal ganglion cells—the primary neurons of interest for retinal cell replacement—were the two major contributing populations among the traced presynaptic cells. This system provides a platform for assessing synaptic connections in cultured retinal neurons and sets the stage for future cell replacement studies aimed at characterizing or enhancing synaptogenesis. Used in this manner, in vitro synaptic tracing is envisioned to complement traditional preclinical animal model testing, which is limited by evolutionary incompatibilities in synaptic machinery inherent to human xenografts.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Re-formation of synaptic connectivity in dissociated human stem cell-derived retinal organoid cultures

Ludwig

Mayerl

Gao

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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“…Retinal degeneration as a result of the death of photoreceptors, specialized cells that provide phototransduction, and retinal pigment epithelium (RPE) is the main cause of many degenerative and dystrophic diseases of the human eye that lead to the loss of eyesight (Fu et al, 2018). Currently, modern medicine is actively developing approaches for the correction of eyesight in this pathology aimed at preserving the original photoreceptors and RPE (Jiang et al, 2018), replacing cells by activating endogenous regeneration (Otteson, 2017), or by cell transplantation (Jiang et al, 2018;Léveillard and Klipfel, 2019). All this became possible because of the development of a number of cell and molecular biology technologies.…”

Section: Introduction Methodological Approaches To the Restoration Omentioning

confidence: 99%

Reprogramming of Differentiated Mammalian and Human Retinal Pigment Epithelium: Current Achievements and Prospects

2020

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Impairment of the homeostatic and functional integrity of the retina and retinal pigment epithelium (RPE) is the main cause of some degenerative diseases of the human eye, which are accompanied by loss of eyesight. Despite the significant progress made over the past decades in the development of new methods for treatment for this pathology, there are still several complications when using surgical methods for correction of eyesight and so far insurmountable limitations in the applications of modern approaches, such as gene therapy and genetic engineering. One of the promising approaches to the treatment of degenerative diseases of the retina may be an approach based on the application of regenerative capacities of its endogenous cells with high plasticity, in particular, of RPE cells and Müller glia. Currently, vertebrate RPE cells are of great interest as a source of new photoreceptors and other neurons in the degrading retina in vivo. In this regard, the possibilities of their direct reprogramming by genetic, epigenetic, and chemical methods and their combination are being investigated. This review focuses on research in gene-directed reprogramming of vertebrate RPE cells into retinal neurons, with detailed analysis of the genes used as the main reprogramming factors, comparative analysis, and extrapolation of experimental data from animals to humans. Also, this review covers studies on the application of alternative approaches to gene-directed reprogramming, such as chemicalmediated reprogramming with the use of cocktails of therapeutic low-molecular-weight compounds and microRNAs. In general, the research results indicate the complexity of the process for direct reprogramming of human RPE cells into retinal neurons. However, taking into account the results of direct reprogramming of vertebrate cells and the accessibility of human RPE cells for various vectors that deliver a variety of molecules to cells, such as transcription factors, chimeric endonucleases, recombinant proteins, and low-weight molecular compounds, the most optimal combination of factors for the successful conversion of human RPE cells to retinal neurons can be suggested.

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“…Retinal degeneration as a result of the death of photoreceptors and RPE is the main cause of many degenerative diseases of the human eye, leading to vision loss [119]. For vision correction during this kind of pathology, approaches are currently being actively developed in contemporary medicine, aimed at preserving the original photoreceptors and RPE [120] and/or striving to replace cells by activating endogenous regeneration [121] or through cell transplantation [120,122]. One approach to treating a number of degenerative retinal diseases, including age-related macular degeneration, is cell replacement therapy.…”

Section: The Potential Of Retinal Pigment Epithelium Cell Subpopulati...mentioning

confidence: 99%

Recent Achievements in the Heterogeneity of Mammalian and Human Retinal Pigment Epithelium: In Search of a Stem Cell

Rzhanova,

Markitantova,

Aleksandrova

2024

Cells

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Retinal pigment epithelium (RPE) cells are important fundamentally for the development and function of the retina. In this regard, the study of the morphological and molecular properties of RPE cells, as well as their regenerative capabilities, is of particular importance for biomedicine. However, these studies are complicated by the fact that, despite the external morphological similarity of RPE cells, the RPE is a population of heterogeneous cells, the molecular genetic properties of which have begun to be revealed by sequencing methods only in recent years. This review carries out an analysis of the data from morphological and molecular genetic studies of the heterogeneity of RPE cells in mammals and humans, which reveals the individual differences in the subpopulations of RPE cells and the possible specificity of their functions. Particular attention is paid to discussing the properties of “stemness,” proliferation, and plasticity in the RPE, which may be useful for uncovering the mechanisms of retinal diseases associated with pathologies of the RPE and finding new ways of treating them.

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Mechanisms Underlying the Visual Benefit of Cell Transplantation for the Treatment of Retinal Degenerations

Cited by 8 publications

References 111 publications

Re-formation of synaptic connectivity in dissociated human stem cell-derived retinal organoid cultures

Re-formation of synaptic connectivity in dissociated human stem cell-derived retinal organoid cultures

Reprogramming of Differentiated Mammalian and Human Retinal Pigment Epithelium: Current Achievements and Prospects

Recent Achievements in the Heterogeneity of Mammalian and Human Retinal Pigment Epithelium: In Search of a Stem Cell

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