Dataset Information

Role of the Internal Limiting Membrane in Structural Engraftment and Topographic Spacing of Transplanted Human Stem Cell-Derived Retinal Ganglion Cells.

ABSTRACT: Retinal ganglion cell (RGC) replacement holds potential for restoring vision lost to optic neuropathy. Transplanted RGCs must undergo neuroretinal integration to receive afferent visual signals for processing and efferent transmission. To date, retinal integration following RGC transplantation has been limited. We sought to overcome key barriers to transplanted human stem cell-derived RGC integration. Following co-culture ex vivo on organotypic mouse retinal explants, human RGCs cluster and extend bundled neurites that remain superficial to the neuroretina, hindering afferent synaptogenesis. To enhance integration, we increased the cellular permeability of the internal limiting membrane (ILM). Extracellular matrix digestion using proteolytic enzymes achieved ILM disruption while minimizing retinal toxicity and preserving glial reactivity. ILM disruption is associated with dispersion rather than clustering of co-cultured RGC bodies and neurites, and increased parenchymal neurite ingrowth. The ILM represents a significant obstacle to transplanted RGC connectivity and its circumvention may be necessary for functional RGC replacement.

SUBMITTER: Zhang KY

PROVIDER: S-EPMC7897583 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Role of the Internal Limiting Membrane in Structural Engraftment and Topographic Spacing of Transplanted Human Stem Cell-Derived Retinal Ganglion Cells.

Zhang Kevin Y KY Tuffy Caitlyn C Mertz Joseph L JL Quillen Sarah S Wechsler Laurence L Quigley Harry A HA Zack Donald J DJ Johnson Thomas V TV

Stem cell reports 20201230 1

Retinal ganglion cell (RGC) replacement holds potential for restoring vision lost to optic neuropathy. Transplanted RGCs must undergo neuroretinal integration to receive afferent visual signals for processing and efferent transmission. To date, retinal integration following RGC transplantation has been limited. We sought to overcome key barriers to transplanted human stem cell-derived RGC integration. Following co-culture ex vivo on organotypic mouse retinal explants, human RGCs cluster and exte ...[more]

PMID: 33382979

Similar Datasets

Project description:Retinal degeneration is the leading cause of untreatable blindness in the developed world. Cell transplantation strategies provide a novel therapeutic approach to repair the retina and restore sight. Previously, we have shown that photoreceptor precursor cells can integrate and form functional photoreceptors after transplantation into the subretinal space of the adult mouse. In a clinical setting, however, it is likely that far greater numbers of integrated photoreceptors would be required to restore visual function. We therefore sought to assess whether the outer limiting membrane (OLM), a natural barrier between the subretinal space and the outer nuclear layer (ONL), could be reversibly disrupted and if disruption of this barrier could lead to enhanced numbers of transplanted photoreceptors integrating into the ONL. Transient chemical disruption of the OLM was induced in adult mice using the glial toxin, dl-alpha-aminoadipic acid (AAA). Dissociated early post-natal neural retinal cells were transplanted via subretinal injection at various time-points after AAA administration. At 3 weeks post-injection, the number of integrated, differentiated photoreceptor cells was assessed and compared with those found in the PBS-treated contralateral eye. We demonstrate for the first time that the OLM can be reversibly disrupted in adult mice, using a specific dose of AAA administered by intravitreal injection. In this model, OLM disruption is maximal at 72 h, and recovers by 2 weeks. When combined with cell transplantation, disruption of the OLM leads to a significant increase in the number of photoreceptors integrated within the ONL compared with PBS-treated controls. This effect was only seen in animals in which AAA had been administered 72 h prior to transplantation, i.e. when precursor cells were delivered into the subretinal space at a time coincident with maximal OLM disruption. These findings suggest that the OLM presents a physical barrier to photoreceptor integration following transplantation into the subretinal space in the adult mouse. Reversible disruption of the OLM may provide a strategy for increasing cell integration in future therapeutic applications.

Project description:BackgroundEpiretinal membranes (ERMs) have been reported after pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment (RRD). Peeling of the internal limiting membrane (ILM) can prevent post-PPV ERM formation but has a potential negative impact on macular structure and function.PurposeTo investigate the anatomical and functional outcomes of ILM peeling during PPV for primary RRD.MethodsThis was a prospective nonrandomized study that included 60 eyes of 60 patients with a primary macula-off RRD and less than grade C proliferative vitreoretinopathy (PVR). Eyes were allocated into 2 groups; Group A underwent PPV without ILM peeling and Group B had ILM peeling. At postoperative month 6, all patients underwent retinal imaging using spectral domain optical coherence tomography (OCT) and OCT angiography and macular function was assessed using multifocal electroretinogram (mfERG). Baseline characteristics and postoperative anatomical and visual outcomes were recorded and statistically analyzed.ResultsWe enrolled 30 eyes of 30 patients in each group. In Group A, mean age was 44.6 years, while the mean age of Group B patients was 49.9 years. Postoperative LogMAR visual acuity was significantly better in Group A than in Group B (p < 0.001). ERMs were demonstrated on OCT in 13.3% of Group A and none of Group B patients (p = 0.04). Retinal dimples were found in 53.3% of Group B and none of Group A eyes (p < 0.001). OCTA showed a greater vessel density of the superficial capillary plexus (SCP) in Group A compared to Group B eyes (p = 0.046), while no difference was found regarding deep capillary vessel density (p = 0.7). Mean amplitude of mfERG P1 wave was significantly higher in Group A eyes than in Group B (p = 0.002). Both the SCP vessel density and P1 amplitude were positively correlated with visual acuity (p < 0.001).ConclusionThis study suggests that ILM peeling prevents ERM development in eyes undergoing PPV for uncomplicated macula-off RRD, but potential damage to macular structure and function were found.Trial registration Retrospectively registered on 09/24/2019 on ClinicalTrials.gov with an ID of NCT04139811.

Dataset Information

Role of the Internal Limiting Membrane in Structural Engraftment and Topographic Spacing of Transplanted Human Stem Cell-Derived Retinal Ganglion Cells.

Publications

Role of the Internal Limiting Membrane in Structural Engraftment and Topographic Spacing of Transplanted Human Stem Cell-Derived Retinal Ganglion Cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets