A5032409568- Retinal Development and Disorders
- Neurogenesis and neuroplasticity mechanisms
- Neuroinflammation and Neurodegeneration Mechanisms
- Zebrafish Biomedical Research Applications
- Pluripotent Stem Cells Research
- CRISPR and Genetic Engineering
- interferon and immune responses
- Genetics, Aging, and Longevity in Model Organisms
- RNA regulation and disease
- Retinal Diseases and Treatments
- Developmental Biology and Gene Regulation
- Traumatic Brain Injury and Neurovascular Disturbances
- Tryptophan and brain disorders
- S100 Proteins and Annexins
- Reproductive Biology and Fertility
- Virus-based gene therapy research
- Pancreatitis Pathology and Treatment
- 3D Surveying and Cultural Heritage
- Urban Planning and Valuation
- Tissue Engineering and Regenerative Medicine
- Immune Response and Inflammation
- Ocular Oncology and Treatments
- Wnt/β-catenin signaling in development and cancer
- Mosquito-borne diseases and control
- Retinal and Optic Conditions
Johns Hopkins University
2022-2025
Johns Hopkins Medicine
2022-2025
The Ohio State University
2016-2022
The Ohio State University Wexner Medical Center
2015-2020
Nationwide Children's Hospital
2020
Injury induces retinal Müller glia of certain cold-blooded vertebrates, but not those mammals, to regenerate neurons. To identify gene regulatory networks that reprogram into progenitor cells, we profiled changes in expression and chromatin accessibility from zebrafish, chick, mice response different stimuli. We identified evolutionarily conserved species-specific controlling glial quiescence, reactivity, neurogenesis. In zebrafish the transition quiescence reactivity is essential for...
Generation of neurons through direct reprogramming has emerged as a promising therapeutic approach for treating neurodegenerative diseases. In this study, we present an efficient method retinal glial cells into neurons. By suppressing Notch signaling by disrupting either Rbpj or Notch1/2 , induced mature Müller to reprogram bipolar- and amacrine-like We demonstrate that directly activates both effector genes specific glia while indirectly repressing expression neurogenic basic...
Microglia and inflammation have context-specific impacts upon neuronal survival in different models of central nervous system (CNS) disease. Herein, we investigate how inflammatory mediators, including microglia, interleukin 1 beta (IL1β), signaling through receptor type (IL-1R1), influence the retinal neurons response to excitotoxic damage.Excitotoxic damage was induced via intraocular injections NMDA. Microglial phenotype were assessed by immunohistochemistry. Single-cell RNA sequencing...
Abstract Müller glia (MG) in mammalian retinas are incapable of regenerating neurons after damage, whereas the MG lower vertebrates regenerate functional neurons. Identification cell signaling pathways and gene regulatory networks that regulate MG‐mediated regeneration is key to harnessing regenerative potential MG. Here, we study how NFkB‐signaling influences glial responses damage reprogramming into rodent retina. We find activation NFkB dynamic expression NFkB‐associated genes however...
Following acute retinal damage, zebrafish possess the ability to regenerate all neuronal subtypes through Müller glia (MG) reprogramming and asymmetric cell division that produces a multipotent glia-derived progenitor (MGPC). This raises three key questions. First, do MG reprogram developmental (RPC) state? Second, what extent does regeneration recapitulate development? And finally, loss of different induce unique responses? We examined these questions by performing single-nuclear...
Abstract Environmental exposure such as cigarette smoke induces epigenetic changes that can induce degenerative heterogeneity and accelerate aging. In early age-related macular degeneration (AMD), the leading worldwide cause of blindness among elderly, retinal pigment epithelial (RPE) cell is a key change. Since smoking strongest environmental risk factor for AMD, we hypothesized RPE through are distinct from aging, with becomes vulnerable to insult. We administered condensate (CSC)...
The mTor pathway is an important cell-signaling that can influence many different cellular processes. We investigate the roles of mTor-signaling in formation Müller glia-derived progenitor cells (MGPCs) retina using chick model system. During embryonic development, pS6 (a readout active mTor-signaling) present early-stage retinal progenitors, differentiating amacrine and ganglion cells, late-stage progenitors or maturing glia. By contrast, at low levels a few scattered cell types mature,...
Retinal regeneration is robust in some cold-blooded vertebrates, but this process ineffective warm-blooded vertebrates. Understanding the mechanisms that suppress reprogramming of Müller glia into neurogenic progenitors key to harnessing regenerative potential retina. Inflammation and reactive microglia are known influence formation glia-derived progenitor cells (MGPCs), underlying interaction unknown. We used a chick vivo model investigate nuclear factor kappa B (NF-κB) signaling, critical...
Abstract Recent studies suggest midkine (MDK) is involved in the development and regeneration of zebrafish retina. We investigate expression patterns MDK related factors, roles neuronal survival, influence upon formation Müller glia‐derived progenitor cells (MGPCs) chick mouse model systems. By using single‐cell RNA‐sequencing, we find that pleiotrophin ( PTN ), a MDK‐related cytokine, are upregulated by glia (MG) during later stages chick. While downregulated, dramatically mature MG after...
Recent studies have demonstrated the impact of pro-inflammatory signaling and reactive microglia/macrophages on formation Müller glial-derived progenitor cells (MGPCs) in retina. In chick retina, ablation prevents MGPCs. Analyses single-cell RNA-sequencing retinal libraries revealed that quiescent activated a significant upon transcriptomic profile glia (MG). damaged monocyte-depleted retinas, MG fail to upregulate genes related different cell pathways, including those Wnt, heparin-binding...
Abstract Müller glia‐derived progenitor cells (MGPCs) have the capability to regenerate neurons in retinas of different vertebrate orders. The formation MGPCs is regulated by a network cell‐signaling pathways. purpose this study was investigate how BMP/Smad1/5/8‐ and TGFβ/Smad2/3‐signaling are coordinated influence chick model system. We find that pSmad1/5/8 selectively up‐regulated nuclei glia following treatment with BMP4, FGF2, or NMDA‐induced damage, up‐regulation blocked dorsomorphin...
ABSTRACT Müller glia can be stimulated to de‐differentiate, proliferate, and form glia‐derived progenitor cells (MGPCs) that are capable of producing retinal neurons. The signaling pathways influence the de‐differentiation mature proliferation MGPCs may include Wnt‐pathway. purpose this study was investigate how Wnt‐signaling influences formation in chick retina vivo . In NMDA‐damaged retinas where known form, we find dynamic changes levels potential readouts Wnt‐signaling, including dkk1 ,...
Retinal Müller glia in cold-blooded vertebrates can reprogram into neurogenic progenitors to replace neurons lost injury, but mammals lack this ability. While recent studies have shown that transgenic overexpression of bHLH factors and glial-specific disruption NFI family transcription Notch signaling induce competence mammalian glia, induction neurogenesis wildtype has thus far proven elusive. Here we report viral-mediated the pluripotency factor Oct4 ( Pou5f1 ) induces transdifferentiation...
Retinal Müller glia in cold-blooded vertebrates can reprogram into neurogenic progenitors to replace neurons lost injury, but mammals lack this ability. While recent studies have shown that transgenic overexpression of bHLH factors and glial-specific disruption NFI family transcription Notch signaling induce competence mammalian glia, induction neurogenesis wildtype has thus far proven elusive. Here, we report viral-mediated the pluripotency factor Pou5f1 (Oct4) induces transdifferentiation...
Retinal Müller glia in cold-blooded vertebrates can reprogram into neurogenic progenitors to replace neurons lost injury, but mammals lack this ability. While recent studies have shown that transgenic overexpression of bHLH factors and glial-specific disruption NFI family transcription Notch signaling induce competence mammalian glia, induction neurogenesis wild-type has thus far proven elusive. Here, we report viral-mediated the pluripotency factor Oct4 ( Pou5f1 ) induces...
Retinal Müller glia in cold-blooded vertebrates can reprogram into neurogenic progenitors to replace neurons lost injury, but mammals lack this ability. While recent studies have shown that transgenic overexpression of bHLH factors and glial-specific disruption NFI family transcription Notch signaling induce competence mammalian glia, induction neurogenesis wildtype has thus far proven elusive. Here, we report viral-mediated the pluripotency factor Pou5f1 (Oct4) induces transdifferentiation...
Many genes are known to regulate retinal regeneration after widespread tissue damage. Conversely, controlling limited cell loss, as per degenerative diseases, undefined. As stem/progenitor responses scale injury levels, understanding how the extent and specificity of loss impact regenerative processes is important. Here, transgenic zebrafish enabling selective ganglion (RGC) ablation were used identify that RGC regeneration. A single multiomics-informed screen 100 identified seven knockouts...
Summary Generation of neurons through direct reprogramming has emerged as a promising therapeutic approach for neurodegenerative diseases. Despite successful applications in vitro , vivo implementation been hampered by low efficiency. In this study, we present highly efficient strategy retinal glial cells into simultaneously inhibiting key negative regulators. By suppressing Notch signaling the removal its central mediator Rbpj, induced mature Müller to reprogram bipolar and amacrine...
Abstract Injury induces retinal Müller glia of cold-blooded, but not mammalian, vertebrates to regenerate neurons. To identify gene regulatory networks that control neuronal reprogramming in glia, we comprehensively profiled injury-dependent changes expression and chromatin accessibility from zebrafish, chick mice using bulk RNA-Seq ATAC-Seq, as well single-cell RNA-Seq. Cross-species integrative analysis these data, together with functional validation, identified evolutionarily conserved...
Abstract Retinal Müller glia in cold-blooded vertebrates can reprogram into neurogenic progenitors to replace neurons lost injury, but mammals lack this ability. While recent studies have shown that transgenic overexpression of bHLH factors and glial-specific disruption NFI family transcription Notch signaling induce competence mammalian glia, induction neurogenesis wildtype has thus far proven elusive. Here we report viral-mediated the pluripotency factor Oct4 ( Pou5f1 ) induces...
Abstract Many genes are known to regulate retinal regeneration following widespread tissue damage. Conversely, controlling limited cell loss, akin disease conditions, undefined. Combining a novel ganglion (RGC) ablation-based glaucoma model, single omics, and rapid CRISPR/Cas9-based knockout methods screen 100 genes, we identified 18 effectors of RGC kinetics. Surprisingly, 32 33 previously known/implicated regulators were not required for replacement; 7 knockouts accelerated regeneration,...