Directly induced human retinal ganglion cells mimic fetal RGCs and are neuroprotective after transplantation in vivo

Luo, Ziming; Chang, Kun-Che; Wu, Siqi; Sun, Catalina; Xia, Xin; Nahmou, Michael; Bian, Minjuan; Wen, Rain R; Zhu, Ying; Shah, Shweta; Tanasă, Bogdan; Wernig, Marius; Goldberg, Jeffrey L

doi:10.1016/j.stemcr.2022.10.011

Cited by 19 publications

(12 citation statements)

References 47 publications

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“…In addition to promoting endogenous RGC survival and axon regeneration, the area of RGC replacement, such as axon regeneration, has also advanced in recent years. Exogeneous primary RGCs or stem cell-derived RGC-like cells have been reported to survive, integrate into the host retinal circuity and present a certain extent of electrophysiological function after transplant [ 141 , 142 , 143 , 144 ]. However, it may be much more challenging to achieve a more advanced state of vision recovery, as visual function is usually shaped during early childhood.…”

Section: Discussionmentioning

confidence: 99%

Optic Nerve Regeneration in Diabetic Retinopathy: Potentials and Challenges Ahead

2023

IJMS

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Diabetic retinopathy (DR), the most common microvascular compilation of diabetes, is the leading cause of vision loss and blindness worldwide. Recent studies indicate that retinal neuron impairment occurs before any noticeable vascular changes in DR, and retinal ganglion cell (RGC) degeneration is one of the earliest signs. Axons of RGCs have little capacity to regenerate after injury, clinically leading the visual functional defects to become irreversible. In the past two decades, tremendous progress has been achieved to enable RGC axon regeneration in animal models of optic nerve injury, which holds promise for neural repair and visual restoration in DR. This review summarizes these advances and discusses the potential and challenges for developing optic nerve regeneration strategies treating DR.

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Section: Discussionmentioning

confidence: 99%

Optic Nerve Regeneration in Diabetic Retinopathy: Potentials and Challenges Ahead

2023

IJMS

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“…Although a few researchers still use these cells [ 28 , 29 ], several journals, including IOVS , Experimental Eye Research and Molecular Vision , stopped publishing articles based on RGC-5-based experiments in the context of ganglion cell research [ 70 , 72 , 73 ]. There are now several successful approaches to culturing RGC, and although this is much more complex, these cells reflect the true phenotype of neuronal cells [ 74 , 75 , 76 ].…”

Section: Discussionmentioning

confidence: 99%

A Case Study from the Past: “The RGC-5 vs. the 661W Cell Line: Similarities, Differences and Contradictions—Are They Really the Same?”

Hurst,

Attrodt,

Bartz-Schmidt

et al. 2023

IJMS

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In the pursuit of identifying the underlying pathways of ocular diseases, the use of cell lines such as (retinal ganglion cell-5) RGC-5 and 661W became a valuable tool, including pathologies like retinal degeneration and glaucoma. In 2001, the establishment of the RGC-5 cell line marked a significant breakthrough in glaucoma research. Over time, however, concerns arose about the true nature of RGC-5 cells, with conflicting findings in the literature regarding their identity as retinal ganglion cells or photoreceptor-like cells. This study aimed to address the controversy surrounding the RGC-5 cell line’s origin and properties by comparing it with the 661W cell line, a known cone photoreceptor model. Both cell lines were differentiated according to two prior published redifferentiation protocols under the same conditions using 500 nM of trichostatin A (TSA) and investigated for their morphological and neuronal marker properties. The results demonstrated that both cell lines are murine, and they exhibited distinct morphological and neuronal marker properties. Notably, the RGC-5 cells showed higher expression of the neuronal marker β-III tubulin and increased Thy-1-mRNA compared with the 661W cells, providing evidence of their different properties. The findings emphasize the importance of verifying the authenticity of cell lines used in ocular research and highlight the risks of contamination and altered cell properties.

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“…Critically, prior work has focused exclusively on analyses of retinal sections (which capture only a fragment of horizontally oriented dendritic arbors) or 2D maximal projection images of retinal flatmounts, which provide no discrimination between cells lying on the surface of the retina versus those which may have migrated below the ILM. 34,36,[62][63][64] Studies in pre-clinical models of RGC injury induced by intravitreal injection of N-methyl-D-aspartate (NMDA) or ocular hypertension show dendritic extension into the GCL, which is described as neuronal engraftment. 62 The methods to determine graft localization and engraftment are inconsistent across published literature, however, and some studies suggest that transplanted RGCs that accumulated on the vitreous side of the ILM are considered to have integrated.…”

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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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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Directly induced human retinal ganglion cells mimic fetal RGCs and are neuroprotective after transplantation in vivo

Cited by 19 publications

References 47 publications

Optic Nerve Regeneration in Diabetic Retinopathy: Potentials and Challenges Ahead

Optic Nerve Regeneration in Diabetic Retinopathy: Potentials and Challenges Ahead

A Case Study from the Past: “The RGC-5 vs. the 661W Cell Line: Similarities, Differences and Contradictions—Are They Really the Same?”

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

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