Introduced chemokine gradients guide transplanted and regenerated retinal neurons toward their natural position in the retina

Soucy, Jonathan R.; Todd, Levi; Kryukov, Emil; Phay, Monichan Hayes; Reh, Thomas A.; Baranov, Petr

doi:10.1101/2022.09.29.510158

Cited by 3 publications

(6 citation statements)

References 84 publications

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“…An alternative to intravitreal transplantation of hRGCs has been proposed by Baranov et al 65 and involves subretinal transplantation of the neuronal graft. By circumventing the ILM altogether, a small number of RGCs can migrate into the inner retina from the subretinal space.…”

Section: Discussionmentioning

confidence: 99%

“…79 BDNF supplementation is neuroprotective to endogenous RGCs following injury, 80,81 and delivery of sustained release BDNF (along with CNTF and GDNF) appears to promote hRGC survival following transplantation. 65 Thus, co-delivery of hRGCs with neurotrophins may improve graft survival at early time points when the neurons are most susceptible to death. This work has some important limitations.…”

Section: Discussionmentioning

confidence: 99%

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Internal limiting membrane disruption facilitates engraftment of transplanted human stem cell derived retinal ganglion cells

Aguzzi

Zhang

Nagalingam

et al. 2022

Preprint

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Retinal ganglion cell (RGC) death causes irreversible vision loss in patients with glaucoma and other forms of optic neuropathy because the mammalian retina and optic nerve lack endogenous regenerative capacity. RGC transplantation and optic nerve regeneration represent a potential translational approach to vision restoration in glaucoma secondary to RGC loss. Functional RGC replacement requires that 1) donor RGCs integrate into the recipient retina and receive synaptic input from afferent bipolar and amacrine cells and that 2) donor RGCs extend their axons and establish synaptic connections to appropriate neurons in the brain. Here, in an effort to address retinal integration, we demonstrate that the internal limiting membrane (ILM) acts as a physical barrier to the integration of transplanted human stem cell-derived RGCs (hRGCs) into the recipient retina following intravitreal transplantation in vivo. To circumvent the ILM barrier, we intravitreally injected the nonspecific protease pronase-E in immunosuppressed adult C57BL/6J mice prior to transplantation of hRGCs. Separately, we also transplanted hRGCs into adult Lama1nmf223mice, which harbor a point mutation in their Lama-α1 gene that causes developmental ILM dysgenesis. We assessed donor hRGC survival and engraftment using 3D reconstructions of confocal z-stacks in retinal flatmounts. Migration of surviving donor RGC somas into the recipient RGC layer significantly increased after proteolytic or developmental ILM disruption. Moreover, lamination of dendritic arbors into the recipient inner plexiform layer was observed exclusively following ILM disruption. To assess the clinical translatability of this finding, we transplanted hRGCs onto postmortem organotypic human retinal explant cultures and observed significantly increased engraftment following proteolytic ILM digestion. These findings enhance our understanding of the barriers faced by transplanted hRGCs in the adult murine and human retina and provide an avenue for clinically translatable regenerative medicine approaches to vision restoration in optic neuropathy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Internal limiting membrane disruption facilitates engraftment of transplanted human stem cell derived retinal ganglion cells

Aguzzi

Zhang

Nagalingam

et al. 2022

Preprint

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“…Single-cell RNA sequencing data analysis was performed in RStudio v. 2022.07.2 (R language v. 4.2.1) using previously published datasets from the human fetal retina (FD59, FD82, FD105) (9). Raw data was processed as previously described (10). For the stages FD82 and FD105, the analysis included both the peripheral and central retina.…”

Section: Single-cell Rna Sequencing Data Analysismentioning

confidence: 99%

“…Using neuroprotective factors in combination with other approaches to modify the retinal microenvironment and stem cell-derived RGC delivery may offer a viable solution to the challenge of RGC replacement. Depending on the model or state of the disease, the retinal microenvironment may also need to be altered to support donor RGC migration, growth, maturation, axon extension, and increased metabolic demands (10). Therefore, the integration of neuroprotective strategies with cell replacement therapies is likely to be a pivotal direction for research and clinical applications.…”

Section: Nevertheless Rgc Replacement By Transplantation Of Either Pr...mentioning

confidence: 99%

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Sustained neurotrophic factor cotreatment enhances donor and host retinal ganglion cell survival in mice

Soucy,

Kriukov,

Oswald

et al. 2024

Preprint

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Retinal ganglion cells (RGCs) lack regenerative capacity in mammals, and their degeneration in glaucoma leads to irreversible blindness. Traditional RGC transplantation has been limited by poor survival rates of transplanted cells in the hostile microenvironment of a diseased retina. Our research identifies brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) as key elements in retinal development and RGC survival through in silico analysis of the single-cell transcriptome of developing human retinas. Although these factors are abundant during development, they diminish in adulthood. Here, we demonstrate that a slow-release formulation of BDNF and GDNF enhances RGC differentiation and survival in vitro and improves RGC transplantation outcomes in mouse models. This co-treatment increased survival and coverage of donor RGCs within the retina and enhanced neurite extension toward the optic nerve head. Lastly, this co-treatment showed neuroprotective effects on host RGCs, preserving retinal function in a model of optic neuropathy. Altogether, our findings suggest that manipulating the retinal microenvironment with slow-release neurotrophic factors holds promise in regenerative medicine for treating glaucoma and other optic neuropathies. This approach not only improves donor cell survival and integration but also provides a neuroprotective benefit to host cells, indicating a significant advancement for glaucoma therapies.

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Retinal ganglion cell repopulation for vision restoration in optic neuropathy: a roadmap from the RReSTORe Consortium

Soucy,

Aguzzi,

Cho

et al. 2023

Mol Neurodegeneration

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Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous system’s limited regenerative capacity. RGC repopulation is a promising therapeutic approach to reverse vision loss from optic neuropathies if the newly introduced neurons can reestablish functional retinal and thalamic circuits. In theory, RGCs might be repopulated through the transplantation of stem cell-derived neurons or via the induction of endogenous transdifferentiation. The RGC Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) Consortium was established to address the challenges associated with the therapeutic repair of the visual pathway in optic neuropathy. In 2022, the RReSTORe Consortium initiated ongoing international collaborative discussions to advance the RGC repopulation field and has identified five critical areas of focus: (1) RGC development and differentiation, (2) Transplantation methods and models, (3) RGC survival, maturation, and host interactions, (4) Inner retinal wiring, and (5) Eye-to-brain connectivity. Here, we discuss the most pertinent questions and challenges that exist on the path to clinical translation and suggest experimental directions to propel this work going forward. Using these five subtopic discussion groups (SDGs) as a framework, we suggest multidisciplinary approaches to restore the diseased visual pathway by leveraging groundbreaking insights from developmental neuroscience, stem cell biology, molecular biology, optical imaging, animal models of optic neuropathy, immunology & immunotolerance, neuropathology & neuroprotection, materials science & biomedical engineering, and regenerative neuroscience. While significant hurdles remain, the RReSTORe Consortium’s efforts provide a comprehensive roadmap for advancing the RGC repopulation field and hold potential for transformative progress in restoring vision in patients suffering from optic neuropathies.

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Introduced chemokine gradients guide transplanted and regenerated retinal neurons toward their natural position in the retina

Cited by 3 publications

References 84 publications

Internal limiting membrane disruption facilitates engraftment of transplanted human stem cell derived retinal ganglion cells

Internal limiting membrane disruption facilitates engraftment of transplanted human stem cell derived retinal ganglion cells

Sustained neurotrophic factor cotreatment enhances donor and host retinal ganglion cell survival in mice

Retinal ganglion cell repopulation for vision restoration in optic neuropathy: a roadmap from the RReSTORe Consortium

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