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Kevin Y. Zhang

Bio: Kevin Y. Zhang is an academic researcher from Johns Hopkins University. The author has contributed to research in topics: Transplantation & Retinal ganglion cell. The author has an hindex of 2, co-authored 4 publications receiving 7 citations. Previous affiliations of Kevin Y. Zhang include Johns Hopkins University School of Medicine.

Papers
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Journal ArticleDOI
TL;DR: In this article, the cellular permeability of the internal limiting membrane (ILM) was increased for retinal ganglion cell (RGC) transplantation, and extracellular matrix digestion using proteolytic enzymes achieved ILM disruption while minimizing retinal toxicity and preserving glial reactivity.
Abstract: Summary 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.

25 citations

Journal ArticleDOI
08 Jun 2021-Cells
TL;DR: The current state of experimental RGC transplantation is summarized in this paper, and a set of standard approaches to quantifying and reporting experimental outcomes is proposed to guide a collective effort toward functional RGC replacement and optic nerve regeneration.
Abstract: As part of the central nervous system, mammalian retinal ganglion cells (RGCs) lack significant regenerative capacity. Glaucoma causes progressive and irreversible vision loss by damaging RGCs and their axons, which compose the optic nerve. To functionally restore vision, lost RGCs must be replaced. Despite tremendous advancements in experimental models of optic neuropathy that have elucidated pathways to induce endogenous RGC neuroprotection and axon regeneration, obstacles to achieving functional visual recovery through exogenous RGC transplantation remain. Key challenges include poor graft survival, low donor neuron localization to the host retina, and inadequate dendritogenesis and synaptogenesis with afferent amacrine and bipolar cells. In this review, we summarize the current state of experimental RGC transplantation, and we propose a set of standard approaches to quantifying and reporting experimental outcomes in order to guide a collective effort to advance the field toward functional RGC replacement and optic nerve regeneration.

16 citations

Journal ArticleDOI
TL;DR: This article examined how retinal neurons, glia, and vasculature interact with individual extracellular matrix constituents at the internal limiting membrane (ILM) and discussed approaches for achieving retinal parenchymal targeting of gene vectors and cell transplants delivered into the vitreous cavity.

12 citations

Journal ArticleDOI
TL;DR: Zhang et al. as mentioned in this paper presented a protocol for ex vivo human RGC transplantation on flatmounted murine organotypic retinal explants, providing a robust platform for studying donor RGC survival, dendritic stratification, topographic distribution, donor-host interactions, and pro-engraftment strategies.
Abstract: Retinal ganglion cell (RGC) transplantation has the potential to restore vision in optic neuropathy, but donor neuron survival and retinal integration remain challenging. Here, we present a protocol for ex vivo human RGC transplantation on flatmounted murine organotypic retinal explants, providing a robust platform for studying donor RGC survival, dendritic stratification, topographic distribution, donor-host interactions, and pro-engraftment strategies. The protocol includes microscopy-based analyses to evaluate donor cell engraftment and can be adapted to various donor cell types or culture systems. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2021a, 2021b).

5 citations

Journal ArticleDOI
15 Aug 2022-ENeuro
TL;DR: These findings identify glaucoma- and IOP-associated functional deficits in an important subcortical RGC projection target and sheds light on the processes linking IOP to vision loss and will be critical for informing future diagnostic approaches and vision-restoration therapies.
Abstract: Abstract Retinal ganglion cell (RGC) axons comprise the optic nerve and carry information to the dorsolateral geniculate nucleus (dLGN), which is then relayed to the cortex for conscious vision. Glaucoma is a blinding neurodegenerative disease that commonly results from intraocular pressure (IOP)-associated injury leading to RGC axonal pathology, disruption of RGC outputs to the brain, and eventual apoptotic loss of RGC somata. The consequences of elevated IOP and glaucomatous pathology on RGC signaling to the dLGN are largely unknown yet are likely to contribute to vision loss. Here, we used anatomic and physiological approaches to study the structure and function of retinogeniculate (RG) synapses in male and female DBA/2J (D2) mice with inherited glaucoma before and after IOP elevation. D2 mice showed progressive loss of anterograde optic tract transport to the dLGN and vGlut2 labeling of RGC axon terminals while patch-clamp measurements of RG synaptic function showed that synaptic transmission was reduced in 9-month and 12-month D2 mice because of the loss of individual RGC axon inputs. TC neuron dendrites had reduced Sholl complexity at 12 months, suggestive of delayed reorganization following reduced synaptic input. There was no detectable change in RGC density in 11- to 12-month D2 retinas, quantified as the number of ganglion cell layer-residing somata immuno-positive for NeuN and immuno-negative for the amacrine marker choline acetyltransferase (ChAT). Thus, observed synaptic defects appear to precede RGC somatic loss. These findings identify glaucoma-associated and IOP-associated deficits in an important subcortical RGC projection target, shedding light on processes linking IOP to vision loss.

2 citations


Cited by
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Journal ArticleDOI
TL;DR: Solving Neurodegeneration as mentioned in this paper is a virtual meeting focused on uncovering common mechanistic roots of neurodegenerative disease and promising targets for new treatments, catalyzed by the goal of finding new treatments for glaucoma, the leading cause of irreversible blindness and the common interest of the three hosting foundations.
Abstract: Abstract Across neurodegenerative diseases, common mechanisms may reveal novel therapeutic targets based on neuronal protection, repair, or regeneration, independent of etiology or site of disease pathology. To address these mechanisms and discuss emerging treatments, in April, 2021, Glaucoma Research Foundation, BrightFocus Foundation, and the Melza M. and Frank Theodore Barr Foundation collaborated to bring together key opinion leaders and experts in the field of neurodegenerative disease for a virtual meeting titled “Solving Neurodegeneration”. This “think-tank” style meeting focused on uncovering common mechanistic roots of neurodegenerative disease and promising targets for new treatments, catalyzed by the goal of finding new treatments for glaucoma, the world’s leading cause of irreversible blindness and the common interest of the three hosting foundations. Glaucoma, which causes vision loss through degeneration of the optic nerve, likely shares early cellular and molecular events with other neurodegenerative diseases of the central nervous system. Here we discuss major areas of mechanistic overlap between neurodegenerative diseases of the central nervous system: neuroinflammation, bioenergetics and metabolism, genetic contributions, and neurovascular interactions. We summarize important discussion points with emphasis on the research areas that are most innovative and promising in the treatment of neurodegeneration yet require further development. The research that is highlighted provides unique opportunities for collaboration that will lead to efforts in preventing neurodegeneration and ultimately vision loss.

46 citations

Journal ArticleDOI
TL;DR: Solving Neurodegeneration as discussed by the authors is a virtual meeting focused on uncovering common mechanistic roots of neurodegenerative disease and promising targets for new treatments, catalyzed by the goal of finding new treatments for glaucoma, the leading cause of irreversible blindness and the common interest of the three hosting foundations.
Abstract: Abstract Across neurodegenerative diseases, common mechanisms may reveal novel therapeutic targets based on neuronal protection, repair, or regeneration, independent of etiology or site of disease pathology. To address these mechanisms and discuss emerging treatments, in April, 2021, Glaucoma Research Foundation, BrightFocus Foundation, and the Melza M. and Frank Theodore Barr Foundation collaborated to bring together key opinion leaders and experts in the field of neurodegenerative disease for a virtual meeting titled “Solving Neurodegeneration”. This “think-tank” style meeting focused on uncovering common mechanistic roots of neurodegenerative disease and promising targets for new treatments, catalyzed by the goal of finding new treatments for glaucoma, the world’s leading cause of irreversible blindness and the common interest of the three hosting foundations. Glaucoma, which causes vision loss through degeneration of the optic nerve, likely shares early cellular and molecular events with other neurodegenerative diseases of the central nervous system. Here we discuss major areas of mechanistic overlap between neurodegenerative diseases of the central nervous system: neuroinflammation, bioenergetics and metabolism, genetic contributions, and neurovascular interactions. We summarize important discussion points with emphasis on the research areas that are most innovative and promising in the treatment of neurodegeneration yet require further development. The research that is highlighted provides unique opportunities for collaboration that will lead to efforts in preventing neurodegeneration and ultimately vision loss.

42 citations

Journal ArticleDOI
TL;DR: Recent advances in strategies that aim to restore optic nerve function and vision in glaucoma through protective, reparative, and regenerative avenues are summarized.
Abstract: We summarize recent advances in strategies that aim to restore optic nerve function and vision in glaucoma through protective, reparative, and regenerative avenues. Neuroprotection relies on identification of early retinal ganglion cell dysfunction, which could prove challenging in the clinic. Cell replacement therapies show promise in restoring lost vision, but some hurdles remain in restoring visual circuitry in the retina and central connections in the brain. Identification and manipulation of intrinsic and extrinsic cellular mechanisms that promote axon regeneration in both resident and transplanted RGCs will drive future advances in vision restoration. Understanding the roles of multiple cell types in the retina that act in concert to promote RGC survival will aid efforts to promote neuronal health and restoration. Effective RGC transplantation, fine tuning axon guidance and growth, and synaptogenesis of transplanted and resident RGCs are still areas that require more research.

18 citations

Journal ArticleDOI
08 Jun 2021-Cells
TL;DR: The current state of experimental RGC transplantation is summarized in this paper, and a set of standard approaches to quantifying and reporting experimental outcomes is proposed to guide a collective effort toward functional RGC replacement and optic nerve regeneration.
Abstract: As part of the central nervous system, mammalian retinal ganglion cells (RGCs) lack significant regenerative capacity. Glaucoma causes progressive and irreversible vision loss by damaging RGCs and their axons, which compose the optic nerve. To functionally restore vision, lost RGCs must be replaced. Despite tremendous advancements in experimental models of optic neuropathy that have elucidated pathways to induce endogenous RGC neuroprotection and axon regeneration, obstacles to achieving functional visual recovery through exogenous RGC transplantation remain. Key challenges include poor graft survival, low donor neuron localization to the host retina, and inadequate dendritogenesis and synaptogenesis with afferent amacrine and bipolar cells. In this review, we summarize the current state of experimental RGC transplantation, and we propose a set of standard approaches to quantifying and reporting experimental outcomes in order to guide a collective effort to advance the field toward functional RGC replacement and optic nerve regeneration.

16 citations

Journal ArticleDOI
TL;DR: This article examined how retinal neurons, glia, and vasculature interact with individual extracellular matrix constituents at the internal limiting membrane (ILM) and discussed approaches for achieving retinal parenchymal targeting of gene vectors and cell transplants delivered into the vitreous cavity.

12 citations