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Bhattacharya S, Deka J, Avallone T, Todd L. The neuroimmune interface in retinal regeneration. Prog Retin Eye Res 2025; 106:101361. [PMID: 40287050 DOI: 10.1016/j.preteyeres.2025.101361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Revised: 04/12/2025] [Accepted: 04/23/2025] [Indexed: 04/29/2025]
Abstract
Retinal neurodegeneration leads to irreversible blindness due to the mammalian nervous system's inability to regenerate lost neurons. Efforts to regenerate retina involve two main strategies: stimulating endogenous cells to reprogram into neurons or transplanting stem-cell derived neurons into the degenerated retina. However, both approaches must overcome a major barrier in getting new neurons to grow back down the optic nerve and connect to appropriate visual targets in environments that differ significantly from developmental conditions. While immune privilege has historically been associated with the central nervous system, an emerging literature highlights the active role of immune cells in shaping neurodegeneration and regeneration. This review explores the neuroimmune interface in retinal repair, dissecting how immune interactions influence glial reprogramming, transplantation outcomes, and axonal regeneration. By integrating insights from regenerative species with mammalian models, we highlight novel immunomodulatory strategies to optimize retinal regeneration.
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Affiliation(s)
- Sucheta Bhattacharya
- Department of Ophthalmology and Visual Sciences, SUNY Upstate Medical University, Syracuse, NY, 13210, USA; Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA
| | - Jugasmita Deka
- Department of Ophthalmology and Visual Sciences, SUNY Upstate Medical University, Syracuse, NY, 13210, USA; Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA
| | - Thomas Avallone
- Department of Ophthalmology and Visual Sciences, SUNY Upstate Medical University, Syracuse, NY, 13210, USA
| | - Levi Todd
- Department of Ophthalmology and Visual Sciences, SUNY Upstate Medical University, Syracuse, NY, 13210, USA; Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA.
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2
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Arrigo A, Cremona O, Aragona E, Casoni F, Consalez G, Dogru RM, Hauck SM, Antropoli A, Bianco L, Parodi MB, Bandello F, Grosche A. Müller cells trophism and pathology as the next therapeutic targets for retinal diseases. Prog Retin Eye Res 2025; 106:101357. [PMID: 40254246 DOI: 10.1016/j.preteyeres.2025.101357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 04/14/2025] [Accepted: 04/15/2025] [Indexed: 04/22/2025]
Abstract
Müller cells are a crucial retinal cell type involved in multiple regulatory processes and functions that are essential for retinal health and functionality. Acting as structural and functional support for retinal neurons and photoreceptors, Müller cells produce growth factors, regulate ion and fluid homeostasis, and facilitate neuronal signaling. They play a pivotal role in retinal morphogenesis and cell differentiation, significantly contributing to macular development. Due to their radial morphology and unique cytoskeletal organization, Müller cells act as optical fibers, efficiently channeling photons directly to the photoreceptors. In response to retinal damage, Müller cells undergo specific gene expression and functional changes that serve as a first line of defense for neurons, but can also lead to unwarranted cell dysfunction, contributing to cell death and neurodegeneration. In some species, Müller cells can reactivate their developmental program, promoting retinal regeneration and plasticity-a remarkable ability that holds promising therapeutic potential if harnessed in mammals. The crucial and multifaceted roles of Müller cells-that we propose to collectively call "Müller cells trophism"-highlight the necessity of maintaining their functionality. Dysfunction of Müller cells, termed "Müller cells pathology," has been associated with a plethora of retinal diseases, including age-related macular degeneration, diabetic retinopathy, vitreomacular disorders, macular telangiectasia, and inherited retinal dystrophies. In this review, we outline how even subtle disruptions in Müller cells trophism can drive the pathological cascade of Müller cells pathology, emphasizing the need for targeted therapies to preserve retinal health and prevent disease progression.
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Affiliation(s)
- Alessandro Arrigo
- Ophthalmology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Eye Repair Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
| | - Ottavio Cremona
- Vita-Salute San Raffaele University, Milan, Italy; Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
| | - Emanuela Aragona
- Ophthalmology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Filippo Casoni
- Vita-Salute San Raffaele University, Milan, Italy; Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giacomo Consalez
- Vita-Salute San Raffaele University, Milan, Italy; Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Rüya Merve Dogru
- Department of Physiological Genomics, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
| | - Stefanie M Hauck
- Metabolomics and Proteomics Core, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, 80939, Germany
| | - Alessio Antropoli
- Ophthalmology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Lorenzo Bianco
- Ophthalmology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | | | - Francesco Bandello
- Ophthalmology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Antje Grosche
- Department of Physiological Genomics, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany.
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Norrie JL, Lupo MS, Little DR, Shirinifard A, Mishra A, Zhang Q, Geiger N, Putnam D, Djekidel N, Ramirez C, Xu B, Dundee JM, Yu J, Chen X, Dyer MA. Latent epigenetic programs in Müller glia contribute to stress and disease response in the retina. Dev Cell 2025; 60:1199-1216.e7. [PMID: 39753128 PMCID: PMC12014377 DOI: 10.1016/j.devcel.2024.12.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 07/09/2024] [Accepted: 12/06/2024] [Indexed: 04/24/2025]
Abstract
Previous studies have demonstrated the dynamic changes in chromatin structure during retinal development correlate with changes in gene expression. However, those studies lack cellular resolution. Here, we integrate single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) with bulk data to identify cell-type-specific changes in chromatin structure during human and murine development. Although promoter activity is correlated with chromatin accessibility, we discovered several hundred genes that were transcriptionally silent but had accessible chromatin at their promoters. Most of those silent/accessible gene promoters were in Müller glial cells, which function to maintain retinal homeostasis and respond to stress, injury, or disease. We refer to these as "pliancy genes" because they allow the Müller glia to rapidly change their gene expression and cellular state in response to retinal insults. The Müller glial cell pliancy program is established during development, and we demonstrate that pliancy genes are important for regulating inflammation in the murine retina in vivo.
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Affiliation(s)
- Jackie L Norrie
- Departments of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Marybeth S Lupo
- Departments of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Danielle R Little
- Departments of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Abbas Shirinifard
- Departments of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Akhilesh Mishra
- Departments of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Qiong Zhang
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Natalie Geiger
- Departments of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Daniel Putnam
- Departments of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Nadhir Djekidel
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Cody Ramirez
- Departments of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Beisi Xu
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Jacob M Dundee
- Departments of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Jiang Yu
- Departments of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Xiang Chen
- Departments of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Michael A Dyer
- Departments of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
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Lee EJ, Kim M, Park S, Shim JH, Cho HJ, Park JA, Park K, Lee D, Kim JH, Jeong H, Matsuzaki F, Kim SY, Kim J, Yang H, Lee JS, Kim JW. Restoration of retinal regenerative potential of Müller glia by disrupting intercellular Prox1 transfer. Nat Commun 2025; 16:2928. [PMID: 40133314 PMCID: PMC11937340 DOI: 10.1038/s41467-025-58290-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 03/17/2025] [Indexed: 03/27/2025] Open
Abstract
Individuals with retinal degenerative diseases struggle to restore vision due to the inability to regenerate retinal cells. Unlike cold-blooded vertebrates, mammals lack Müller glia (MG)-mediated retinal regeneration, indicating the limited regenerative capacity of mammalian MG. Here, we identify prospero-related homeobox 1 (Prox1) as a key factor restricting this process. Prox1 accumulates in MG of degenerating human and mouse retinas but not in regenerating zebrafish. In mice, Prox1 in MG originates from neighboring retinal neurons via intercellular transfer. Blocking this transfer enables MG reprogramming into retinal progenitor cells in injured mouse retinas. Moreover, adeno-associated viral delivery of an anti-Prox1 antibody, which sequesters extracellular Prox1, promotes retinal neuron regeneration and delays vision loss in a retinitis pigmentosa model. These findings establish Prox1 as a barrier to MG-mediated regeneration and highlight anti-Prox1 therapy as a promising strategy for restoring retinal regeneration in mammals.
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Affiliation(s)
- Eun Jung Lee
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
- KAIST Stem Cell Research Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
- Celliaz Ltd., Daejeon, South Korea
| | - Museong Kim
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
- KAIST Stem Cell Research Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
| | - Sooyeon Park
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
- KAIST Stem Cell Research Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
- Celliaz Ltd., Daejeon, South Korea
| | | | - Hyun-Ju Cho
- Microbiome Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea
- KRIBB School, University of Science and Technology, Daejeon, South Korea
| | | | - Kihyun Park
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
| | - Dongeun Lee
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
- KAIST Stem Cell Research Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
| | - Jeong Hwan Kim
- Korea Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea
| | - Haeun Jeong
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
- KAIST Stem Cell Research Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
| | - Fumio Matsuzaki
- Laboratory for Cell Asymmetry, RIKEN Centre for Biosystems Dynamics Research, Kobe, Hyogo, Japan
- Department of Aging Science and Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Seon-Young Kim
- Korea Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea
| | - Jaehoon Kim
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
| | - Hanseul Yang
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
- KAIST Stem Cell Research Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
| | - Jeong-Soo Lee
- Microbiome Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea
- KRIBB School, University of Science and Technology, Daejeon, South Korea
| | - Jin Woo Kim
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea.
- KAIST Stem Cell Research Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea.
- Celliaz Ltd., Daejeon, South Korea.
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5
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Ventura ALM, Silva TM, França GR. Cannabinoids Activate Endoplasmic Reticulum Stress Response and Promote the Death of Avian Retinal Müller Cells in Culture. Brain Sci 2025; 15:291. [PMID: 40149812 PMCID: PMC11940308 DOI: 10.3390/brainsci15030291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 02/28/2025] [Accepted: 03/07/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND/OBJECTIVES Activation of cannabinoid CB1 or CB2 receptors induces the death of glial progenitors from the chick retina in culture. Here, by using an enriched retinal glial cell culture, we characterized some mechanisms underlying glial death promoted by cannabinoids. METHODS AND RESULTS Retinal cultures obtained from 8-day-old (E8) chick embryos and maintained for 12-15 days (C12-15) were used. MTT assays revealed that the CB1/CB2 agonist WIN 55,212-2 (WIN) decreased cell viability in the cultures in a time-dependent manner, with a concomitant increase in extracellular LDH activity, suggesting membrane integrity loss. Cell death was also dose-dependently induced by cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC), and CP55940, another CB1/CB2 agonist. In contrast to WIN-induced cell death that was not blocked by either antagonist, the deleterious effect of CBD was blocked by the CB2 receptor antagonist SR144528, but not by PF514273, a CB1 receptor antagonist. WIN-treated cultures showed glial cells with large vacuoles in cytoplasm that were absent in cultures incubated with WIN plus 4-phenyl-butyrate (PBA), a chemical chaperone. Since cannabinoids induced the phosphorylation of eukaryotic initiation factor 2-alfa (eIF2α), these results suggest a process of endoplasmic reticulum (ER) swelling and stress. Incubation of the cultures with WIN for 4 h induced a ~five-fold increase in the number of cells labeled with the ROS indicator CM-H2DCFDA. WIN induced the phosphorylation of JNK but not of p38 in the cultures, and also induced an increase in the number of glial cells expressing cleaved-caspase 3 (c-CASP3). The decrease in cell viability and the expression of c-CASP3 was blocked by salubrinal, an inhibitor of eIF2α dephosphorylation. CONCLUSIONS These data suggest that cannabinoids induce the apoptosis of glial cells in culture by promoting ROS production, ER stress, JNK phosphorylation, and caspase-3 processing. The graphical abstract was created at Biorender.com.
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Affiliation(s)
- Ana Lúcia Marques Ventura
- Neuroscience Program, Department of Neurobiology, Federal Fluminense University, Niterói CEP 24210-201, RJ, Brazil;
| | - Thayane Martins Silva
- Neuroscience Program, Department of Neurobiology, Federal Fluminense University, Niterói CEP 24210-201, RJ, Brazil;
| | - Guilherme Rapozeiro França
- Department of Physiological Sciences, Federal University of the State of Rio de Janeiro, Rio de Janeiro CEP 20211-040, RJ, Brazil;
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Taylor OB, El‐Hodiri HM, Palazzo I, Todd L, Fischer AJ. Regulating the formation of Müller glia-derived progenitor cells in the retina. Glia 2025; 73:4-24. [PMID: 39448874 PMCID: PMC11660542 DOI: 10.1002/glia.24635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 09/18/2024] [Accepted: 09/28/2024] [Indexed: 10/26/2024]
Abstract
We summarize recent findings in different animal models regarding the different cell-signaling pathways and gene networks that influence the reprogramming of Müller glia into proliferating, neurogenic progenitor cells in the retina. Not surprisingly, most of the cell-signaling pathways that guide the proliferation and differentiation of embryonic retinal progenitors also influence the ability of Müller glia to become proliferating Müller glia-derived progenitor cells (MGPCs). Further, the neuronal differentiation of MGPC progeny is potently inhibited by networks of neurogenesis-suppressing genes in chick and mouse models but occurs freely in zebrafish. There are important differences between the model systems, particularly pro-inflammatory signals that are active in mature Müller glia in damaged rodent and chick retinas, but less so in fish retinas. These pro-inflammatory signals are required to initiate the process of reprogramming, but if sustained suppress the potential of Müller glia to become neurogenic MGPCs. Further, there are important differences in how activated Müller glia up- or downregulate pro-glial transcription factors in the different model systems. We review recent findings regarding regulatory cell signaling and gene networks that influence the activation of Müller glia and the transition of these glia into proliferating progenitor cells with neurogenic potential in fish, chick, and mouse model systems.
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Affiliation(s)
- Olivia B. Taylor
- Department of NeuroscienceCollege of Medicine, The Ohio State UniversityColumbusOhioUSA
- Neuroscience Graduate ProgramThe Ohio State UniversityColumbusOhioUSA
| | - Heithem M. El‐Hodiri
- Department of NeuroscienceCollege of Medicine, The Ohio State UniversityColumbusOhioUSA
| | - Isabella Palazzo
- The Solomon H. Snyder Department of NeuroscienceJohns Hopkins University School of MedicineBaltimoreMassachusettsUSA
| | - Levi Todd
- Department of Ophthalmology and Visual SciencesSUNY Upstate Medical UniversitySyracuseNew YorkUSA
| | - Andy J. Fischer
- Department of NeuroscienceCollege of Medicine, The Ohio State UniversityColumbusOhioUSA
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Salman A, Bolinches‐Amorós A, Storm T, Moralli D, Bryika P, Russell AJ, Davies SG, Barnard AR, MacLaren RE. Spontaneously Immortalised Nonhuman Primate Müller Glia Cell Lines as Source to Explore Retinal Reprogramming Mechanisms for Cell Therapies. J Cell Physiol 2025; 240:e31482. [PMID: 39605294 PMCID: PMC11774137 DOI: 10.1002/jcp.31482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 10/18/2024] [Accepted: 10/24/2024] [Indexed: 11/29/2024]
Abstract
Cell replacement therapies for ocular diseases characterised by photoreceptors degeneration are challenging due to poor primary cell survival in culture. A stable retinal cell source to replace lost photoreceptors holds promise. Müller glia cells play a pivotal role in retinal homoeostasis by providing metabolic and structural support to retinal neurons, preventing aberrant photoreceptors migration, and facilitating safe glutamate uptake. In fish and amphibians, injured retinas regenerate due to Müller-like glial stem cells, a phenomenon absent in the mammalian retina for unknown reasons. Research on Müller cells has been complex due to difficulties in obtaining pure cell population and their rapid de-differentiation in culture. While various Müller glia cell lines from human and rats are described, no nonhuman primate Müller glia cell line is currently available. Here, we report spontaneously immortalised Müller glia cell lines derived from macaque neural retinas that respond to growth factors and expand indefinitely in culture. They exhibit Müller cells morphology, such as an elongated shape and cytoplasmic projections, express Müller glia markers (VIMENTIN, GLUTAMINE SYNTHASE, glutamate-aspartate transporter, and CD44), and express stem cell markers such as PAX6 and SOX2. In the presence of factors that induce photoreceptor differentiation, these cells show a shift in gene expression patterns suggesting a state of de-differentiation, a phenomenon known in reprogrammed mammalian Müller cells. The concept of self-renewing retina might seem unfeasible, but not unprecedented. While vertebrate Müller glia have a regeneration potential absent in mammals, understanding the mechanisms behind reprogramming of Müller glia in mammals could unlock their potential for treating retinal degenerative diseases.
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Affiliation(s)
- Ahmed Salman
- Nuffield Department of Clinical NeurosciencesUniversity of OxfordOxfordOxfordshireUK
| | - Arantxa Bolinches‐Amorós
- Nuffield Department of Clinical NeurosciencesUniversity of OxfordOxfordOxfordshireUK
- Welcome Centre for Human GeneticsUniversity of OxfordOxfordOxfordshireUK
| | - Tina Storm
- Nuffield Department of Clinical NeurosciencesUniversity of OxfordOxfordOxfordshireUK
| | - Daniela Moralli
- Department of ChemistryUniversity of OxfordOxfordOxfordshireUK
| | - Paulina Bryika
- Department of ChemistryUniversity of OxfordOxfordOxfordshireUK
| | - Angela J. Russell
- Welcome Centre for Human GeneticsUniversity of OxfordOxfordOxfordshireUK
- Department of PharmacologyUniversity of OxfordOxfordOxfordshireUK
| | | | - Alun R. Barnard
- Nuffield Department of Clinical NeurosciencesUniversity of OxfordOxfordOxfordshireUK
| | - Robert E. MacLaren
- Nuffield Department of Clinical NeurosciencesUniversity of OxfordOxfordOxfordshireUK
- Oxford Eye HospitalOxfordOxfordshireUK
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8
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Chen P, Ji J, Chen X, Zhang J, Wen X, Liu L. Retinal glia in myopia: current understanding and future directions. Front Cell Dev Biol 2024; 12:1512988. [PMID: 39759766 PMCID: PMC11696152 DOI: 10.3389/fcell.2024.1512988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 12/02/2024] [Indexed: 01/07/2025] Open
Abstract
Myopia, a major public health problem, involves axial elongation and thinning of all layers of the eye, including sclera, choroid and retina, which defocuses incoming light and thereby blurs vision. How the various populations of glia in the retina are involved in the disorder is unclear. Astrocytes and Müller cells provide structural support to the retina. Astrogliosis in myopia may influence blood oxygen supply, neuronal function, and axon diameter, which in turn may affect signal conduction. Müller cells act as a sensor of mechanical stretching in myopia and trigger downstream molecular responses. Microglia, for their part, may exhibit a reactive morphology and elevated response to inflammation in myopia. This review assesses current knowledge about how myopia may involve retinal glia, and it explores directions for future research into that question.
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Affiliation(s)
- Pengfan Chen
- Department of Ophthalmology, Laboratory of Optometry and Vision Sciences, Department of Optometry and Visual Science. West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jing Ji
- Department of Ophthalmology, Laboratory of Optometry and Vision Sciences, Department of Optometry and Visual Science. West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xinyi Chen
- West China school of Medicine, Sichuan University, Chengdu, Sichuan, China
| | - Jiali Zhang
- Department of Ophthalmology, Laboratory of Optometry and Vision Sciences, Department of Optometry and Visual Science. West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiangyi Wen
- Department of Ophthalmology, Laboratory of Optometry and Vision Sciences, Department of Optometry and Visual Science. West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Longqian Liu
- Department of Ophthalmology, Laboratory of Optometry and Vision Sciences, Department of Optometry and Visual Science. West China Hospital, Sichuan University, Chengdu, Sichuan, China
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9
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Sarusie MVK, Rönnbäck C, Jespersgaard C, Baungaard S, Ali Y, Kessel L, Christensen ST, Brøndum-Nielsen K, Møllgård K, Rosenberg T, Larsen LA, Grønskov K. A novel GFAP frameshift variant identified in a family with optico-retinal dysplasia and vision impairment. Hum Mol Genet 2024; 33:2145-2158. [PMID: 39471354 DOI: 10.1093/hmg/ddae134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 08/22/2024] [Accepted: 09/17/2024] [Indexed: 11/01/2024] Open
Abstract
Gain-of-function variants in GFAP leads to protein aggregation and is the cause of the severe neurodegenerative disorder Alexander Disease (AxD), while loss of GFAP function has been considered benign. Here, we investigated a six-generation family, where multiple individuals presented with gliosis of the optic nerve head and visual impairment. Whole genome sequencing (WGS) revealed a frameshift variant in GFAP (c.928dup, p.(Met310Asnfs*113)) segregating with disease. Analysis of human embryonic tissues revealed strong expression of GFAP in retinal neural progenitors. A zebrafish model verified that c.928dup does not result in extensive GFAP protein aggregation and zebrafish gfap loss-of-function mutants showed vision impairment and retinal dysplasia, characterized by a significant loss of Müller glia cells and photoreceptor cells. Our findings show how different mutational mechanisms can cause diverging phenotypes and reveal a novel function of GFAP in vertebrate eye development.
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Affiliation(s)
- Menachem V K Sarusie
- Department of Clinical Genetics, Kennedy Center, Rigshospitalet, University of Copenhagen, Gamle Landevej 7, 2600 Glostrup, Denmark
- Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Cecilia Rönnbäck
- Department of Ophthalmology, Rigshospitalet-Glostrup, University of Copenhagen, Valdemar Hansens Vej 13, 2600 Glostrup, Denmark
| | - Cathrine Jespersgaard
- Department of Clinical Genetics, Kennedy Center, Rigshospitalet, University of Copenhagen, Gamle Landevej 7, 2600 Glostrup, Denmark
| | - Sif Baungaard
- Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Yeasmeen Ali
- Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark
| | - Line Kessel
- Department of Ophthalmology, Rigshospitalet-Glostrup, University of Copenhagen, Valdemar Hansens Vej 13, 2600 Glostrup, Denmark
- Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark
| | - Søren T Christensen
- Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark
| | - Karen Brøndum-Nielsen
- Department of Clinical Genetics, Kennedy Center, Rigshospitalet, University of Copenhagen, Gamle Landevej 7, 2600 Glostrup, Denmark
| | - Kjeld Møllgård
- Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Thomas Rosenberg
- Department of Ophthalmology, Rigshospitalet-Glostrup, University of Copenhagen, Valdemar Hansens Vej 13, 2600 Glostrup, Denmark
| | - Lars A Larsen
- Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Karen Grønskov
- Department of Clinical Genetics, Kennedy Center, Rigshospitalet, University of Copenhagen, Gamle Landevej 7, 2600 Glostrup, Denmark
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10
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Russo B, D'Addato G, Salvatore G, Menduni M, Frontoni S, Carbone L, Camaioni A, Klinger FG, De Felici M, Picconi F, La Sala G. Gliotic Response and Reprogramming Potential of Human Müller Cell Line MIO-M1 Exposed to High Glucose and Glucose Fluctuations. Int J Mol Sci 2024; 25:12877. [PMID: 39684590 DOI: 10.3390/ijms252312877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 11/25/2024] [Accepted: 11/27/2024] [Indexed: 12/18/2024] Open
Abstract
Retinal neurodegeneration (RN), an early marker of diabetic retinopathy (DR), is closely associated with Müller glia cells (MGs) in diabetic subjects. MGs play a pivotal role in maintaining retinal homeostasis, integrity, and metabolic support and respond to diabetic stress. In lower vertebrates, MGs have a strong regenerative response and can completely repair the retina after injuries. However, this ability diminishes as organisms become more complex. The aim of this study was to investigate the gliotic response and reprogramming potential of the human Müller cell line MIO-M1 cultured in normoglycemic (5 mM glucose, NG) and hyperglycemic (25 mM glucose, HG) conditions and then exposed to sustained high-glucose and glucose fluctuation (GF) treatments to mimic the human diabetic conditions. The results showed that NG MIO-M1 cells exhibited a dynamic activation to sustained high-glucose and GF treatments by increasing GFAP and Vimentin expression together, indicative of gliotic response. Increased expression of SHH and SOX2 were also observed, foreshadowing reprogramming potential. Conversely, HG MIO-M1 cells showed increased levels of the indexes reported above and adaptation/desensitization to sustained high-glucose and GF treatments. These findings indicate that MIO-M1 cells exhibit a differential response under various glucose treatments, which is dependent on the metabolic environment. The in vitro model used in this study, based on a well-established cell line, enables the exploration of how these responses occur in a controlled, reproducible system and the identification of strategies to promote neurogenesis over neurodegeneration. These findings contribute to the understanding of MGs responses under diabetic conditions, which may have implications for future therapeutic approaches to diabetes-associated retinal neurodegeneration.
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Affiliation(s)
- Benedetta Russo
- Unit of Endocrinology and Diabetology, Isola Tiberina-Gemelli Isola Hospital, 00186 Rome, Italy
| | - Giorgia D'Addato
- Section of Histology and Embryology, Saint Camillus International University of Health Sciences, 00131 Rome, Italy
| | - Giulia Salvatore
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Marika Menduni
- Unit of Endocrinology and Diabetology, Isola Tiberina-Gemelli Isola Hospital, 00186 Rome, Italy
| | - Simona Frontoni
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Luigi Carbone
- Unit of Emergency Room, Emergency Medicine and Internal Medicine, Isola Tiberina-Gemelli Isola Hospital, 00186 Rome, Italy
| | - Antonella Camaioni
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Francesca Gioia Klinger
- Section of Histology and Embryology, Saint Camillus International University of Health Sciences, 00131 Rome, Italy
| | - Massimo De Felici
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Fabiana Picconi
- Unit of Endocrinology and Diabetology, Isola Tiberina-Gemelli Isola Hospital, 00186 Rome, Italy
| | - Gina La Sala
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy
- CNR Institute of Biochemistry and Cell Biology, 00015 Rome, Italy
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11
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Jui J, Goldman D. Müller Glial Cell-Dependent Regeneration of the Retina in Zebrafish and Mice. Annu Rev Genet 2024; 58:67-90. [PMID: 38876121 DOI: 10.1146/annurev-genet-111523-102000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2024]
Abstract
Sight is one of our most precious senses. People fear losing their sight more than any other disability. Thus, restoring sight to the blind is an important goal of vision scientists. Proregenerative species, such as zebrafish, provide a system for studying endogenous mechanisms underlying retina regeneration. Nonregenerative species, such as mice, provide a system for testing strategies for stimulating retina regeneration. Key to retina regeneration in zebrafish and mice is the Müller glial cell, a malleable cell type that is amenable to a variety of regenerative strategies. Here, we review cellular and molecular mechanisms used by zebrafish to regenerate a retina, as well as the application of these mechanisms, and other strategies to stimulate retina regeneration in mice. Although our focus is on Müller glia (MG), niche components and their impact on MG reprogramming are also discussed.
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Affiliation(s)
- Jonathan Jui
- Molecular Neuroscience Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, USA; ,
| | - Daniel Goldman
- Molecular Neuroscience Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, USA; ,
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12
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An MJ, Kim JY, Kim J, Kim DH, Shin GS, Lee HM, Jo AR, Park Y, Hwangbo Y, Kim CH, Kim MJ, Jung YS, Kim J, Rhee S, Seo SB, Kim JW. Reorganization of H3K9me heterochromatin leads to neuronal impairment via the cascading destruction of the KDM3B-centered epigenomic network. iScience 2024; 27:110380. [PMID: 39165843 PMCID: PMC11334829 DOI: 10.1016/j.isci.2024.110380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 03/14/2024] [Accepted: 06/24/2024] [Indexed: 08/22/2024] Open
Abstract
Histone H3K9 methylated heterochromatin silences repetitive non-coding sequences and lineage-specific genes during development, but how tissue-specific genes escape from heterochromatin in differentiated cells is unclear. Here, we examine age-dependent transcriptomic profiling of terminally differentiated mouse retina to identify epigenetic regulators involved in heterochromatin reorganization. The single-cell RNA sequencing analysis reveals a gradual downregulation of Kdm3b in cone photoreceptors during aging. Disruption of Kdm3b (Kdm3b +/- ) of 12-month-old mouse retina leads to the decreasing number of cones via apoptosis, and it changes the morphology of cone ribbon synapses. Integration of the transcriptome with epigenomic analysis in Kdm3b +/- retinas demonstrates gains of heterochromatin features in synapse assembly and vesicle transport genes that are downregulated via the accumulation of H3K9me1/2. Contrarily, losses of heterochromatin in apoptotic genes exacerbated retinal neurodegeneration. We propose that the KDM3B-centered epigenomic network is crucial for balancing of cone photoreceptor homeostasis via the modulation of gene set-specific heterochromatin features during aging.
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Affiliation(s)
- Mi-Jin An
- Department of Life Science, Chung-Ang University, Seoul 06974, South Korea
| | - Ji-Young Kim
- Department of Life Science, Chung-Ang University, Seoul 06974, South Korea
| | - Jinho Kim
- Department of Life Science, Chung-Ang University, Seoul 06974, South Korea
| | - Dae-Hyun Kim
- Department of Life Science, Chung-Ang University, Seoul 06974, South Korea
| | - Geun-Seup Shin
- Department of Life Science, Chung-Ang University, Seoul 06974, South Korea
| | - Hyun-Min Lee
- Department of Life Science, Chung-Ang University, Seoul 06974, South Korea
| | - Ah-Ra Jo
- Department of Life Science, Chung-Ang University, Seoul 06974, South Korea
| | - Yuna Park
- Department of Life Science, Chung-Ang University, Seoul 06974, South Korea
| | - Yujeong Hwangbo
- Department of Life Science, Chung-Ang University, Seoul 06974, South Korea
| | - Chul-Hong Kim
- Department of Life Science, Chung-Ang University, Seoul 06974, South Korea
| | - Mi Jin Kim
- Department of Life Science, Chung-Ang University, Seoul 06974, South Korea
| | - Youn-Sang Jung
- Department of Life Science, Chung-Ang University, Seoul 06974, South Korea
| | - Jeongkyu Kim
- Department of Life Science, Chung-Ang University, Seoul 06974, South Korea
| | - Sangmyung Rhee
- Department of Life Science, Chung-Ang University, Seoul 06974, South Korea
| | - Sang-Beom Seo
- Department of Life Science, Chung-Ang University, Seoul 06974, South Korea
| | - Jung-Woong Kim
- Department of Life Science, Chung-Ang University, Seoul 06974, South Korea
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13
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Taylor OB, Patel SP, Hawthorn EC, El-Hodiri HM, Fischer AJ. ID factors regulate the ability of Müller glia to become proliferating neurogenic progenitor-like cells. Glia 2024; 72:1236-1258. [PMID: 38515287 PMCID: PMC11334223 DOI: 10.1002/glia.24523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 02/26/2024] [Accepted: 02/28/2024] [Indexed: 03/23/2024]
Abstract
The purpose of this study was to investigate how ID factors regulate the ability of Müller glia (MG) to reprogram into proliferating MG-derived progenitor cells (MGPCs) in the chick retina. We found that ID1 is transiently expressed by maturing MG (mMG), whereas ID4 is maintained in mMG in embryonic retinas. In mature retinas, ID4 was prominently expressed by resting MG, but following retinal damage ID4 was rapidly upregulated and then downregulated in MGPCs. By contrast, ID1, ID2, and ID3 were low in resting MG and then upregulated in MGPCs. Inhibition of ID factors following retinal damage decreased numbers of proliferating MGPCs. Inhibition of IDs, after MGPC proliferation, significantly increased numbers of progeny that differentiated as neurons. In damaged or undamaged retinas inhibition of IDs increased levels of p21Cip1 in MG. In response to damage or insulin+FGF2 levels of CDKN1A message and p21Cip1 protein were decreased, absent in proliferating MGPCs, and elevated in MG returning to a resting phenotype. Inhibition of notch- or gp130/Jak/Stat-signaling in damaged retinas increased levels of ID4 but not p21Cip1 in MG. Although ID4 is the predominant isoform expressed by MG in the chick retina, id1 and id2a are predominantly expressed by resting MG and downregulated in activated MG and MGPCs in zebrafish retinas. We conclude that ID factors have a significant impact on regulating the responses of MG to retinal damage, controlling the ability of MG to proliferate by regulating levels of p21Cip1, and suppressing the neurogenic potential of MGPCs.
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Affiliation(s)
- Olivia B. Taylor
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
| | - Snehal P. Patel
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
| | - Evan C. Hawthorn
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
| | - Heithem M. El-Hodiri
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
| | - Andy J. Fischer
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
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14
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Liang S, Zhou J, Yu X, Lu S, Liu R. Neuronal conversion from glia to replenish the lost neurons. Neural Regen Res 2024; 19:1446-1453. [PMID: 38051886 PMCID: PMC10883502 DOI: 10.4103/1673-5374.386400] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 08/16/2023] [Indexed: 12/07/2023] Open
Abstract
ABSTRACT Neuronal injury, aging, and cerebrovascular and neurodegenerative diseases such as cerebral infarction, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis, and Huntington's disease are characterized by significant neuronal loss. Unfortunately, the neurons of most mammals including humans do not possess the ability to self-regenerate. Replenishment of lost neurons becomes an appealing therapeutic strategy to reverse the disease phenotype. Transplantation of pluripotent neural stem cells can supplement the missing neurons in the brain, but it carries the risk of causing gene mutation, tumorigenesis, severe inflammation, and obstructive hydrocephalus induced by brain edema. Conversion of neural or non-neural lineage cells into functional neurons is a promising strategy for the diseases involving neuron loss, which may overcome the above-mentioned disadvantages of neural stem cell therapy. Thus far, many strategies to transform astrocytes, fibroblasts, microglia, Müller glia, NG2 cells, and other glial cells to mature and functional neurons, or for the conversion between neuronal subtypes have been developed through the regulation of transcription factors, polypyrimidine tract binding protein 1 (PTBP1), and small chemical molecules or are based on a combination of several factors and the location in the central nervous system. However, some recent papers did not obtain expected results, and discrepancies exist. Therefore, in this review, we discuss the history of neuronal transdifferentiation, summarize the strategies for neuronal replenishment and conversion from glia, especially astrocytes, and point out that biosafety, new strategies, and the accurate origin of the truly converted neurons in vivo should be focused upon in future studies. It also arises the attention of replenishing the lost neurons from glia by gene therapies such as up-regulation of some transcription factors or down-regulation of PTBP1 or drug interference therapies.
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Affiliation(s)
- Shiyu Liang
- National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China
- School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing, China
| | - Jing Zhou
- Department of Geriatric Rehabilitation, Beijing Rehabilitation Hospital, Capital Medical University, Beijing, China
| | - Xiaolin Yu
- National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China
| | - Shuai Lu
- National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China
| | - Ruitian Liu
- National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China
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15
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Arias-Montecino A, Sykes A, Álvarez-Hernán G, de Mera-Rodríguez JA, Calle-Guisado V, Martín-Partido G, Rodríguez-León J, Francisco-Morcillo J. Histological and scanning electron microscope observations on the developing retina of the cuttlefish (Sepia officinalis Linnaeus, 1758). Tissue Cell 2024; 88:102417. [PMID: 38820948 DOI: 10.1016/j.tice.2024.102417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 05/03/2024] [Accepted: 05/20/2024] [Indexed: 06/02/2024]
Abstract
In this work we present a detailed study of the major events during retinal histogenesis of the cuttlefish Sepia officinalis from early embryos to newly hatched animals and juveniles. For this purpose, we carried out morphometric and histological analyses using light and scanning electron microscopy. From St19, the first embryonic stage analysed, to St23/24 the embryonic retina is composed of a pseudostratified epithelium showing abundant mitotic figures in the more internal surface. At St24 the first photoreceptor nuclei appear in the presumptive inner segment layer, while an incipient layer of apical processes of the future rhabdomeric layer become visible at St25. From this stage onwards, both the rhabdomeric layer and the inner segment layer increase in size until postnatal ages. In contrast, the width of the supporting cell layer progressively decreases from St25/26 until postnatal ages. S. officinalis embryos hatched in a morphologically advanced state, showing a differentiated retina even in the last stages of the embryonic period. However, features of immaturity are still observable in the retinal tissue during the first postnatal weeks of life, such as the existence of mitotic figures in the apical region of the supporting cell layer and migrating nuclei of differentiating photoreceptors crossing the basal membrane to reach their final location in the inner segment layer. Therefore, postnatal retinal neurogenesis is present in juvenile specimens of S. officinalis.
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Affiliation(s)
- Alejandro Arias-Montecino
- Área de Biología Celular, Departamento de Anatomía, Biología Celular y Zoología, Facultad de Ciencias, Universidad de Extremadura, Badajoz 06006, Spain
| | - Antonio Sykes
- Center of Marine Sciences, Universidade do Algarve Campus de Gambelas, Faro 8005-139, Portugal
| | - Guadalupe Álvarez-Hernán
- Área de Anatomía y Embriología Humana, Departamento de Anatomía, Biología Celular y Zoología, Facultad de Medicina, Universidad de Extremadura, Badajoz 06006, Spain.
| | - José Antonio de Mera-Rodríguez
- Área de Biología Celular, Departamento de Anatomía, Biología Celular y Zoología, Facultad de Ciencias, Universidad de Extremadura, Badajoz 06006, Spain
| | - Violeta Calle-Guisado
- Área de Anatomía y Embriología Humana, Departamento de Anatomía, Biología Celular y Zoología, Facultad de Medicina, Universidad de Extremadura, Badajoz 06006, Spain
| | - Gervasio Martín-Partido
- Área de Biología Celular, Departamento de Anatomía, Biología Celular y Zoología, Facultad de Ciencias, Universidad de Extremadura, Badajoz 06006, Spain
| | - Joaquín Rodríguez-León
- Área de Anatomía y Embriología Humana, Departamento de Anatomía, Biología Celular y Zoología, Facultad de Medicina, Universidad de Extremadura, Badajoz 06006, Spain
| | - Javier Francisco-Morcillo
- Área de Biología Celular, Departamento de Anatomía, Biología Celular y Zoología, Facultad de Ciencias, Universidad de Extremadura, Badajoz 06006, Spain
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16
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Kelly LE, El-Hodiri HM, Crider A, Fischer AJ. Protein phosphatases regulate the formation of Müller glia-derived progenitor cells in the chick retina. Mol Cell Neurosci 2024; 129:103932. [PMID: 38679247 PMCID: PMC11362962 DOI: 10.1016/j.mcn.2024.103932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/26/2024] [Accepted: 04/18/2024] [Indexed: 05/01/2024] Open
Abstract
Different kinase-dependent cell signaling pathways are known to play important roles in glia-mediated neuroprotection and reprogramming of Müller glia (MG) into Müller glia-derived progenitor cells (MGPCs) in the retina. However, very little is known about the phosphatases that regulate kinase-dependent signaling in MG. Using single-cell RNA-sequencing (scRNA-seq) databases, we investigated patterns of expression of Dual Specificity Phosphatases (DUSP1/6) and other protein phosphatases in normal and damaged chick retinas. We found that DUSP1, DUSP6, PPP3CB, PPP3R1 and PPPM1A/B/D/E/G are widely expressed by many types of retinal neurons and are dynamically expressed by MG and MGPCs in retinas during the process of reprogramming. We find that inhibition of DUSP1/6 and PP2C phosphatases enhances the formation of proliferating MGPCs in damaged retinas and in retinas treated with insulin and FGF2 in the absence of damage. By contrast, inhibition of PP2B phosphatases suppressed the formation of proliferating MGPCs, but increased numbers of proliferating MGPCs in undamaged retinas treated with insulin and FGF2. In damaged retinas, inhibition of DUSP1/6 increased levels of pERK1/2 and cFos in MG whereas inhibition of PP2B's decreased levels of pStat3 and pS6 in MG. Analyses of scRNA-seq libraries identified numerous differentially activated gene modules in MG in damaged retinas versus MG in retinas treated with insulin+FGF2 suggesting significant differences in kinase-dependent signaling pathways that converge on the formation of MGPCs. Inhibition of phosphatases had no significant effects upon numbers of dying cells in damaged retinas. We conclude that the activity of different protein phosphatases acting through retinal neurons and MG "fine-tune" the cell signaling responses of MG in damaged retinas and during the reprogramming of MG into MGPCs.
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Affiliation(s)
- Lisa E Kelly
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Heithem M El-Hodiri
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Andrew Crider
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Andy J Fischer
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH, USA.
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17
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Bovi Dos Santos G, de Lima-Vasconcellos TH, Móvio MI, Birbrair A, Del Debbio CB, Kihara AH. New Perspectives in Stem Cell Transplantation and Associated Therapies to Treat Retinal Diseases: From Gene Editing to 3D Bioprinting. Stem Cell Rev Rep 2024; 20:722-737. [PMID: 38319527 DOI: 10.1007/s12015-024-10689-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/29/2024] [Indexed: 02/07/2024]
Abstract
Inherited and non-inherited retinopathies can affect distinct cell types, leading to progressive cell death and visual loss. In the last years, new approaches have indicated exciting opportunities to treat retinopathies. Cell therapy in retinitis pigmentosa, age-related macular disease, and glaucoma have yielded encouraging results in rodents and humans. The first two diseases mainly impact the photoreceptors and the retinal pigmented epithelium, while glaucoma primarily affects the ganglion cell layer. Induced pluripotent stem cells and multipotent stem cells can be differentiated in vitro to obtain specific cell types for use in transplant as well as to assess the impact of candidate molecules aimed at treating retinal degeneration. Moreover, stem cell therapy is presented in combination with newly developed methods, such as gene editing, Müller cells dedifferentiation, sheet & drug delivery, virus-like particles, optogenetics, and 3D bioprinting. This review describes the recent advances in this field, by presenting an updated panel based on cell transplants and related therapies to treat retinopathies.
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Affiliation(s)
- Gabrieli Bovi Dos Santos
- Laboratório de Neurogenética, Universidade Federal do ABC, São Bernardo do Campo, Santo André, SP, Brazil
| | | | - Marília Inês Móvio
- Laboratório de Neurogenética, Universidade Federal do ABC, São Bernardo do Campo, Santo André, SP, Brazil
| | - Alexander Birbrair
- Department of Dermatology, Medical Sciences Center, University of Wisconsin-Madison, Rm 4385, 1300 University Avenue, Madison, WI, 53706, USA
| | - Carolina Beltrame Del Debbio
- Departamento de Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, Universidade de São Paulo USP, São Paulo, SP, Brazil
| | - Alexandre Hiroaki Kihara
- Laboratório de Neurogenética, Universidade Federal do ABC, São Bernardo do Campo, Santo André, SP, Brazil.
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18
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Guo YM, Jiang X, Min J, Huang J, Huang XF, Ye L. Advances in the study of Müller glia reprogramming in mammals. Front Cell Neurosci 2023; 17:1305896. [PMID: 38155865 PMCID: PMC10752929 DOI: 10.3389/fncel.2023.1305896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 11/27/2023] [Indexed: 12/30/2023] Open
Abstract
Müller cells play an integral role in the development, maintenance, and photopic signal transmission of the retina. While lower vertebrate Müller cells can differentiate into various types of retinal neurons to support retinal repair following damage, there is limited neurogenic potential of mammalian Müller cells. Therefore, it is of great interest to harness the neurogenic potential of mammalian Müller cells to achieve self-repair of the retina. While multiple studies have endeavored to induce neuronal differentiation and proliferation of mammalian Müller cells under defined conditions, the efficiency and feasibility of these methods often fall short, rendering them inadequate for the requisites of retinal repair. As the mechanisms and methodologies of Müller cell reprogramming have been extensively explored, a summary of the reprogramming process of unlocking the neurogenic potential of Müller cells can provide insight into Müller cell fate development and facilitate their therapeutic use in retinal repair. In this review, we comprehensively summarize the progress in reprogramming mammalian Müller cells and discuss strategies for optimizing methods and enhancing efficiency based on the mechanisms of fate regulation.
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Affiliation(s)
- Yi-Ming Guo
- Shaanxi Eye Hospital, Xi’an People’s Hospital (Xi’an Fourth Hospital), Affiliated People’s Hospital of Northwest University, Xi’an, China
| | - Xinyi Jiang
- Department of Neonatology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jie Min
- Shaanxi Eye Hospital, Xi’an People’s Hospital (Xi’an Fourth Hospital), Affiliated People’s Hospital of Northwest University, Xi’an, China
| | - Juan Huang
- Shaanxi Eye Hospital, Xi’an People’s Hospital (Xi’an Fourth Hospital), Affiliated People’s Hospital of Northwest University, Xi’an, China
| | - Xiu-Feng Huang
- Zhejiang Provincial Clinical Research Center for Pediatric Disease, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lu Ye
- Shaanxi Eye Hospital, Xi’an People’s Hospital (Xi’an Fourth Hospital), Affiliated People’s Hospital of Northwest University, Xi’an, China
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19
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Kelly LE, El-Hodiri HM, Crider A, Fischer AJ. Protein phosphatases regulate the formation of Müller glia-derived progenitor cells in the chick retina. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.11.570629. [PMID: 38168320 PMCID: PMC10760049 DOI: 10.1101/2023.12.11.570629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Different kinase-dependent cell signaling pathways are known to play important roles in glia-mediated neuroprotection and reprogramming of Müller glia (MG) into Müller glia-derived progenitor cells (MGPCs) in the retina. However, very little is known about the phosphatases that regulate kinase-dependent signaling in MG. Using single-cell RNA-sequencing (scRNA-seq) databases, we investigated patterns of expression of Dual Specificity Phosphatases (DUSP1/6) and other protein phosphatases in normal and damaged chick retinas. We found that DUSP1, DUSP6, PPP3CB, PPP3R1 and PPPM1A/B/D/E/G are dynamically expressed by MG and MGPCs in retinas during the process of reprogramming. We find that inhibition of DUSP1/6 and PP2C phosphatases enhances the formation of proliferating MGPCs in damaged retinas and in retinas treated with insulin in FGF2 in the absence of damage. By contrast, inhibition of PP2B phosphatases suppressed the formation of proliferating MGPCs, but increased numbers of proliferating MGPCs in undamaged retinas treated with insulin and FGF2. In damaged retinas, inhibition of DUSP1/6 increased levels of pERK1/2 and cFos in MG whereas inhibition of PP2B's decreased levels of pStat3 and pS6 in MG. Analyses of scRNA-seq libraries identified numerous differentially activated gene modules in MG in damaged retinas versus MG in retinas treated with insulin+FGF2 suggesting significant differences in kinase-dependent signaling pathways that converge on the formation of MGPCs. Inhibition of phosphatases had no significant effects upon numbers of dying cells in damaged retinas. We conclude that the activity of different protein phosphatases "fine-tune" the cell signaling responses of MG in damaged retinas and during the reprogramming of MG into MGPCs.
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Affiliation(s)
- Lisa E. Kelly
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
| | - Heithem M. El-Hodiri
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
| | - Andrew Crider
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
| | - Andy J. Fischer
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
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20
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Lee J, Lee BK, Gross JM. Brd activity regulates Müller glia-dependent retinal regeneration in zebrafish. Glia 2023; 71:2866-2883. [PMID: 37584502 DOI: 10.1002/glia.24457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 07/28/2023] [Accepted: 07/31/2023] [Indexed: 08/17/2023]
Abstract
The zebrafish retina possesses tremendous regenerative potential. Müller glia underlie retinal regeneration through their ability to reprogram and generate multipotent neuronal progenitors that re-differentiate into lost neurons. Many factors required for Müller glia reprogramming and proliferation have been identified; however, we know little about the epigenetic and transcriptional regulation of these genes during regeneration. Here, we determined whether transcriptional regulation by members of the Bromodomain (Brd) family is required for Müller glia-dependent retinal regeneration. Our data demonstrate that three brd genes were expressed in Müller glia upon injury. brd2a and brd2b were expressed in all Müller glia and brd4 was expressed only in reprogramming Müller glia. Utilizing (+)-JQ1, a pharmacological inhibitor of Brd function, we demonstrate that transcriptional regulation by Brds plays a critical role in Müller glia reprogramming and regeneration. (+)-JQ1 treatment prevented cell cycle re-entry of Müller glia and the generation of neurogenic progenitors. Modulating the (+)-JQ1 exposure window, we identified the first 48 h post-injury as the time-period during which Müller glia reprogramming occurs. (+)-JQ1 treatments after 48 h post-injury had no effect on the re-differentiation of UV cones, indicating that Brd function is required only for Müller glia reprogramming and not subsequent specification/differentiation events. Brd inhibition also prevented the expression of reprogramming genes like ascl1a and lepb in Müller glia, but not effector genes like mmp9, nor did it affect microglial recruitment after injury. These results demonstrate that transcriptional regulation by Brds plays a critical role during Müller glia-dependent retinal regeneration in zebrafish.
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Affiliation(s)
- Jiwoon Lee
- Departments of Ophthalmology and Developmental Biology, Louis J. Fox Center for Vision Restoration, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Bum-Kyu Lee
- Department of Biomedical Sciences, Cancer Research Center, University at Albany, State University of New York, Rensselaer, New York, USA
| | - Jeffrey M Gross
- Departments of Ophthalmology and Developmental Biology, Louis J. Fox Center for Vision Restoration, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, USA
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21
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El-Hodiri HM, Bentley JR, Reske AG, Taylor OB, Palazzo I, Campbell WA, Halloy NR, Fischer AJ. Heparin-binding epidermal growth factor and fibroblast growth factor 2 rescue Müller glia-derived progenitor cell formation in microglia- and macrophage-ablated chick retinas. Development 2023; 150:dev202070. [PMID: 37971210 PMCID: PMC10730090 DOI: 10.1242/dev.202070] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 11/02/2023] [Indexed: 11/19/2023]
Abstract
Recent studies have demonstrated the impact of pro-inflammatory signaling and reactive microglia/macrophages on the formation of Müller glial-derived progenitor cells (MGPCs) in the retina. In chick retina, ablation of microglia/macrophages prevents the formation of MGPCs. Analyses of single-cell RNA-sequencing chick retinal libraries revealed that quiescent and activated microglia/macrophages have a significant impact upon the transcriptomic profile of Müller glia (MG). In damaged monocyte-depleted retinas, MG fail to upregulate genes related to different cell signaling pathways, including those related to Wnt, heparin-binding epidermal growth factor (HBEGF), fibroblast growth factor (FGF) and retinoic acid receptors. Inhibition of GSK3β, to simulate Wnt signaling, failed to rescue the deficit in MGPC formation, whereas application of HBEGF or FGF2 completely rescued the formation of MGPCs in monocyte-depleted retinas. Inhibition of Smad3 or activation of retinoic acid receptors partially rescued the formation of MGPCs in monocyte-depleted retinas. We conclude that signals produced by reactive microglia/macrophages in damaged retinas stimulate MG to upregulate cell signaling through HBEGF, FGF and retinoic acid, and downregulate signaling through TGFβ/Smad3 to promote the reprogramming of MG into proliferating MGPCs.
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Affiliation(s)
- Heithem M. El-Hodiri
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43221, USA
| | - James R. Bentley
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43221, USA
| | - Alana G. Reske
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43221, USA
| | - Olivia B. Taylor
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43221, USA
| | - Isabella Palazzo
- Solomon Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Warren A. Campbell
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43221, USA
| | - Nicklaus R. Halloy
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43221, USA
| | - Andy J. Fischer
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43221, USA
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22
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Abstract
The neural retina of mammals, like most of the rest of the central nervous system, does not regenerate new neurons after they are lost through damage or disease. The ability of nonmammalian vertebrates, like fish and amphibians, is remarkable, and lessons learned over the last 20 years have revealed some of the mechanisms underlying this potential. This knowledge has recently been applied to mammals to develop methods that can stimulate regeneration in mice. In this review, we highlight the progress in this area, and propose a "wish list" of how the clinical implementation of regenerative strategies could be applicable to various human retinal diseases.
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Affiliation(s)
- Marina Pavlou
- Department of Biological Structure, University of Washington School of Medicine, Institute of Stem Cells and Regenerative Medicine, Seattle, Washington 98195, USA
| | - Thomas A Reh
- Department of Biological Structure, University of Washington School of Medicine, Institute of Stem Cells and Regenerative Medicine, Seattle, Washington 98195, USA
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23
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Norrie JL, Lupo M, Shirinifard A, Djekidel N, Ramirez C, Xu B, Dundee JM, Dyer MA. Latent Epigenetic Programs in Müller Glia Contribute to Stress, Injury, and Disease Response in the Retina. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.15.562396. [PMID: 37905050 PMCID: PMC10614790 DOI: 10.1101/2023.10.15.562396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/02/2023]
Abstract
Previous studies have demonstrated the dynamic changes in chromatin structure during retinal development that correlate with changes in gene expression. However, a major limitation of those prior studies was the lack of cellular resolution. Here, we integrate single-cell (sc) RNA-seq and scATAC-seq with bulk retinal data sets to identify cell type-specific changes in the chromatin structure during development. Although most genes' promoter activity is strongly correlated with chromatin accessibility, we discovered several hundred genes that were transcriptionally silent but had accessible chromatin at their promoters. Most of those silent/accessible gene promoters were in the Müller glial cells. The Müller cells are radial glia of the retina and perform a variety of essential functions to maintain retinal homeostasis and respond to stress, injury, or disease. The silent/accessible genes in Müller glia are enriched in pathways related to inflammation, angiogenesis, and other types of cell-cell signaling and were rapidly activated when we tested 15 different physiologically relevant conditions to mimic retinal stress, injury, or disease in human and murine retinae. We refer to these as "pliancy genes" because they allow the Müller glia to rapidly change their gene expression and cellular state in response to different types of retinal insults. The Müller glial cell pliancy program is established during development, and we demonstrate that pliancy genes are necessary and sufficient for regulating inflammation in the murine retina in vivo. In zebrafish, Müller glia can de-differentiate and form retinal progenitor cells that replace lost neurons. The pro-inflammatory pliancy gene cascade is not activated in zebrafish Müller glia following injury, and we propose a model in which species-specific pliancy programs underly the differential response to retinal damage in species that can regenerate retinal neurons (zebrafish) versus those that cannot (humans and mice).
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24
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Kerschensteiner D. Losing, preserving, and restoring vision from neurodegeneration in the eye. Curr Biol 2023; 33:R1019-R1036. [PMID: 37816323 PMCID: PMC10575673 DOI: 10.1016/j.cub.2023.08.044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/12/2023]
Abstract
The retina is a part of the brain that sits at the back of the eye, looking out onto the world. The first neurons of the retina are the rod and cone photoreceptors, which convert changes in photon flux into electrical signals that are the basis of vision. Rods and cones are frequent targets of heritable neurodegenerative diseases that cause visual impairment, including blindness, in millions of people worldwide. This review summarizes the diverse genetic causes of inherited retinal degenerations (IRDs) and their convergence onto common pathogenic mechanisms of vision loss. Currently, there are few effective treatments for IRDs, but recent advances in disparate areas of biology and technology (e.g., genome editing, viral engineering, 3D organoids, optogenetics, semiconductor arrays) discussed here enable promising efforts to preserve and restore vision in IRD patients with implications for neurodegeneration in less approachable brain areas.
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Affiliation(s)
- Daniel Kerschensteiner
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO 63110, USA.
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25
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Xiao X, Liao Z, Zou J. Genetic and epigenetic regulators of retinal Müller glial cell reprogramming. ADVANCES IN OPHTHALMOLOGY PRACTICE AND RESEARCH 2023; 3:126-133. [PMID: 37846362 PMCID: PMC10577857 DOI: 10.1016/j.aopr.2023.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/18/2023] [Accepted: 05/29/2023] [Indexed: 10/18/2023]
Abstract
Background Retinal diseases characterized with irreversible loss of retinal nerve cells, such as optic atrophy and retinal degeneration, are the main causes of blindness. Current treatments for these diseases are very limited. An emerging treatment strategy is to induce the reprogramming of Müller glial cells to generate new retinal nerve cells, which could potentially restore vision. Main text Müller glial cells are the predominant glial cells in retinae and play multiple roles to maintain retinal homeostasis. In lower vertebrates, such as in zebrafish, Müller glial cells can undergo cell reprogramming to regenerate new retinal neurons in response to various damage factors, while in mammals, this ability is limited. Interestingly, with proper treatments, Müller glial cells can display the potential for regeneration of retinal neurons in mammalian retinae. Recent studies have revealed that dozens of genetic and epigenetic regulators play a vital role in inducing the reprogramming of Müller glial cells in vivo. This review summarizes these critical regulators for Müller glial cell reprogramming and highlights their differences between zebrafish and mammals. Conclusions A number of factors have been identified as the important regulators in Müller glial cell reprogramming. The early response of Müller glial cells upon acute retinal injury, such as the regulation in the exit from quiescent state, the initiation of reactive gliosis, and the re-entry of cell cycle of Müller glial cells, displays significant difference between mouse and zebrafish, which may be mediated by the diverse regulation of Notch and TGFβ (transforming growth factor-β) isoforms and different chromatin accessibility.
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Affiliation(s)
- Xueqi Xiao
- Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou, China
| | - Zhiyong Liao
- Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou, China
| | - Jian Zou
- Department of Ophthalmology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- The Institute of Translational Medicine, Zhejiang University, Hangzhou, China
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26
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Zhang H, Guo Y, Yang Y, Wang Y, Zhang Y, Zhuang J, Zhang Y, Shen M, Zhao J, Zhang R, Qiu Y, Li S, Hu J, Li W, Wu J, Xu H, Fliesler SJ, Liao Y, Liu Z. MAP4Ks inhibition promotes retinal neuron regeneration from Müller glia in adult mice. NPJ Regen Med 2023; 8:36. [PMID: 37443319 DOI: 10.1038/s41536-023-00310-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
Mammalian Müller glia (MG) possess limited regenerative capacities. However, the intrinsic capacity of mammalian MG to transdifferentiate to generate mature neurons without transgenic manipulations remains speculative. Here we show that MAP4K4, MAP4K6 and MAP4K7, which are conserved Misshapen subfamily of ste20 kinases homologs, repress YAP activity in mammalian MG and therefore restrict their ability to be reprogrammed. However, by treating with a small molecule inhibitor of MAP4K4/6/7, mouse MG regain their ability to proliferate and enter into a retinal progenitor cell (RPC)-like state after NMDA-induced retinal damage; such plasticity was lost in YAP knockout MG. Moreover, spontaneous trans-differentiation of MG into retinal neurons expressing both amacrine and retinal ganglion cell (RGC) markers occurs after inhibitor withdrawal. Taken together, these findings suggest that MAP4Ks block the reprogramming capacity of MG in a YAP-dependent manner in adult mammals, which provides a novel avenue for the pharmaceutical induction of retinal regeneration in vivo.
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Affiliation(s)
- Houjian Zhang
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China
- Xiamen University Affiliated Xiamen Eye Center, School of Medicine, Xiamen University, Xiamen, China
- Department of Ophthalmology, the First Affiliated Hospital of University of South China, Hengyang, Hunan, 421001, China
| | - Yuli Guo
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China
- Xiamen University Affiliated Xiamen Eye Center, School of Medicine, Xiamen University, Xiamen, China
- Department of Ophthalmology, the First Affiliated Hospital of University of South China, Hengyang, Hunan, 421001, China
| | - Yaqiong Yang
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China
| | - Yuqian Wang
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China
| | - Youwen Zhang
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China
| | - Jingbin Zhuang
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China
| | - Yuting Zhang
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China
| | - Mei Shen
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China
| | - Jiankai Zhao
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China
| | - Rongrong Zhang
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China
| | - Yan Qiu
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China
| | - Shiying Li
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China
| | - Jiaoyue Hu
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China
| | - Wei Li
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China
| | - Jianfeng Wu
- Laboratory animal research center, Xiamen University, Xiamen, Fujian, 361102, China
| | - Haiwei Xu
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China
| | - Steven J Fliesler
- Departments of Ophthalmology and Biochemistry and Neuroscience Graduate School, Jacobs School of Medicine and Biomedical Sciences, SUNY- University at Buffalo, Buffalo, NY, USA
- Research Service, VA Western New York Healthcare System, Buffalo, NY, USA
| | - Yi Liao
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China.
| | - Zuguo Liu
- Department of Ophthalmology, Xiang'an Hospital of Xiamen University; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China.
- Xiamen University Affiliated Xiamen Eye Center, School of Medicine, Xiamen University, Xiamen, China.
- Department of Ophthalmology, the First Affiliated Hospital of University of South China, Hengyang, Hunan, 421001, China.
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27
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Campbell WA, El-Hodiri HM, Torres D, Hawthorn EC, Kelly LE, Volkov L, Akanonu D, Fischer AJ. Chromatin access regulates the formation of Müller glia-derived progenitor cells in the retina. Glia 2023; 71:1729-1754. [PMID: 36971459 PMCID: PMC11335016 DOI: 10.1002/glia.24366] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 03/06/2023] [Accepted: 03/12/2023] [Indexed: 03/29/2023]
Abstract
Chromatin access and epigenetic control over gene expression play important roles in regulating developmental processes. However, little is known about how chromatin access and epigenetic gene silencing influence mature glial cells and retinal regeneration. Herein, we investigate the expression and functions of S-adenosylhomocysteine hydrolase (SAHH; AHCY) and histone methyltransferases (HMTs) during the formation of Müller glia (MG)-derived progenitor cells (MGPCs) in the chick and mouse retinas. In chick, AHCY, AHCYL1 and AHCYL2, and many different HMTs are dynamically expressed by MG and MGPCs in damaged retinas. Inhibition of SAHH reduced levels of H3K27me3 and potently blocks the formation of proliferating MGPCs. By using a combination of single cell RNA-seq and single cell ATAC-seq, we find significant changes in gene expression and chromatin access in MG with SAHH inhibition and NMDA-treatment; many of these genes are associated with glial and neuronal differentiation. A strong correlation across gene expression, chromatin access, and transcription factor motif access in MG was observed for transcription factors known to convey glial identity and promote retinal development. By comparison, in the mouse retina, inhibition of SAHH has no influence on the differentiation of neuron-like cells from Ascl1-overexpressing MG. We conclude that in the chick the activity of SAHH and HMTs are required for the reprogramming of MG into MGPCs by regulating chromatin access to transcription factors associated with glial differentiation and retinal development.
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Affiliation(s)
- Warren A. Campbell
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
| | - Heithem M. El-Hodiri
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
| | - Diego Torres
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
| | - Evan C. Hawthorn
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
| | - Lisa E. Kelly
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
| | - Leo Volkov
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
| | - David Akanonu
- Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI
| | - Andy J. Fischer
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
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28
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El-Hodiri HM, Bentley J, Reske A, Palazzo I, Campbell WA, Halloy NR, Fischer AJ. Formation of Müller glia-derived progenitor cells in retinas depleted of microglia. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.08.544205. [PMID: 37333380 PMCID: PMC10274900 DOI: 10.1101/2023.06.08.544205] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/20/2023]
Abstract
Recent studies have demonstrated the complex coordination of pro-inflammatory signaling and reactive microglia/macrophage on the formation Müller glial-derived progenitor cells (MGPCs) in the retinas of fish, birds and mice. We generated scRNA-seq libraries to identify transcriptional changes in Müller glia (MG) that result from the depletion of microglia from the chick retina. We found significant changes in different networks of genes in MG in normal and damaged retinas when the microglia are ablated. We identified a failure of MG to upregulate Wnt-ligands, Heparin binding epidermal growth factor (HBEGF), Fibroblast growth factor (FGF), retinoic acid receptors and genes related to Notch-signaling. Inhibition of GSK3β, to simulate Wnt-signaling, failed to rescue the deficit in formation of proliferating MGPCs in damaged retinas missing microglia. By comparison, application of HBEGF or FGF2 completely rescued the formation of proliferating MGPCs in microglia-depleted retinas. Similarly, injection of a small molecule inhibitor to Smad3 or agonist to retinoic acid receptors partially rescued the formation of proliferating MGPCs in microglia-depleted damaged retinas. According to scRNA-seq libraries, patterns of expression of ligands, receptors, signal transducers and/or processing enzymes to cell-signaling via HBEGF, FGF, retinoic acid and TGFβ are rapidly and transiently upregulated by MG after neuronal damage, consistent with important roles for these cell-signaling pathways in regulating the formation of MGPCs. We conclude that quiescent and activated microglia have a significant impact upon the transcriptomic profile of MG. We conclude that signals produced by reactive microglia in damaged retinas stimulate MG to upregulate cell signaling through HBEGF, FGF and retinoic acid, and downregulate signaling through TGFβ/Smad3 to promote the reprogramming on MG into proliferating MGPCs.
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Affiliation(s)
- Heithem M. El-Hodiri
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
| | - James Bentley
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
| | - Alana Reske
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
| | - Isabella Palazzo
- Solomon Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD
| | - Warren A. Campbell
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
| | - Nicklaus R. Halloy
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
| | - Andy J. Fischer
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH
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29
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Li R, Liu J, Yi P, Yang X, Chen J, Zhao C, Liao X, Wang X, Xu Z, Lu H, Li H, Zhang Z, Liu X, Xiang J, Hu K, Qi H, Yu J, Yang P, Hou S. Integrative Single-Cell Transcriptomics and Epigenomics Mapping of the Fetal Retina Developmental Dynamics. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2206623. [PMID: 37017569 DOI: 10.1002/advs.202206623] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 02/24/2023] [Indexed: 06/04/2023]
Abstract
The underlying mechanisms that determine gene expression and chromatin accessibility in retinogenesis are poorly understood. Herein, single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin sequencing are performed on human embryonic eye samples obtained 9-26 weeks after conception to explore the heterogeneity of retinal progenitor cells (RPCs) and neurogenic RPCs. The differentiation trajectory from RPCs to 7 major types of retinal cells are verified. Subsequently, diverse lineage-determining transcription factors are identified and their gene regulatory networks are refined at the transcriptomic and epigenomic levels. Treatment of retinospheres, with the inhibitor of RE1 silencing transcription factor, X5050, induces more neurogenesis with the regular arrangement, and a decrease in Müller glial cells. The signatures of major retinal cells and their correlation with pathogenic genes associated with multiple ocular diseases, including uveitis and age-related macular degeneration are also described. A framework for the integrated exploration of single-cell developmental dynamics of the human primary retina is provided.
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Affiliation(s)
- Ruonan Li
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
- Chongqing Key Laboratory of Ophthalmology, Chongqing, 400016, P. R. China
- Chongqing Eye Institute, Chongqing, 400016, P. R. China
- Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, 400016, P. R. China
| | - Jiangyi Liu
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
- Chongqing Key Laboratory of Ophthalmology, Chongqing, 400016, P. R. China
- Chongqing Eye Institute, Chongqing, 400016, P. R. China
- Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, 400016, P. R. China
| | - Ping Yi
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, P. R. China
| | - Xianli Yang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, P. R. China
| | - Jun Chen
- Department of Obstetrics, Women and Children's Hospital of Chongqing Medical University, Chongqing, 401147, P. R. China
| | - Chenyang Zhao
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
- Chongqing Key Laboratory of Ophthalmology, Chongqing, 400016, P. R. China
- Chongqing Eye Institute, Chongqing, 400016, P. R. China
- Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, 400016, P. R. China
| | - Xingyun Liao
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
- Chongqing Key Laboratory of Ophthalmology, Chongqing, 400016, P. R. China
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, 400030, P. R. China
| | - Xiaotang Wang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
- Chongqing Key Laboratory of Ophthalmology, Chongqing, 400016, P. R. China
- Chongqing Eye Institute, Chongqing, 400016, P. R. China
- Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, 400016, P. R. China
| | - Zongren Xu
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
- Chongqing Key Laboratory of Ophthalmology, Chongqing, 400016, P. R. China
| | - Huiping Lu
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
- Chongqing Key Laboratory of Ophthalmology, Chongqing, 400016, P. R. China
- Chongqing Eye Institute, Chongqing, 400016, P. R. China
- Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, 400016, P. R. China
| | - Hongshun Li
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
- Chongqing Key Laboratory of Ophthalmology, Chongqing, 400016, P. R. China
- Chongqing Eye Institute, Chongqing, 400016, P. R. China
- Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, 400016, P. R. China
| | - Zhi Zhang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
- Chongqing Key Laboratory of Ophthalmology, Chongqing, 400016, P. R. China
- Chongqing Eye Institute, Chongqing, 400016, P. R. China
- Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, 400016, P. R. China
| | - Xianyang Liu
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
- Chongqing Key Laboratory of Ophthalmology, Chongqing, 400016, P. R. China
- Chongqing Eye Institute, Chongqing, 400016, P. R. China
- Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, 400016, P. R. China
| | - Junjie Xiang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
- Chongqing Key Laboratory of Ophthalmology, Chongqing, 400016, P. R. China
- Chongqing Eye Institute, Chongqing, 400016, P. R. China
- Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, 400016, P. R. China
| | - Ke Hu
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
- Chongqing Key Laboratory of Ophthalmology, Chongqing, 400016, P. R. China
- Chongqing Eye Institute, Chongqing, 400016, P. R. China
- Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, 400016, P. R. China
| | - Hongbo Qi
- Department of Obstetrics, Women and Children's Hospital of Chongqing Medical University, Chongqing, 401147, P. R. China
- Chongqing Key Laboratory of Maternal and Fetal Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Jia Yu
- State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, 100005, P. R. China
- The Key Laboratory of RNA and Hematopoietic Regulation, Chinese Academy of Medical Sciences, Beijing, 100005, P. R. China
| | - Peizeng Yang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
- Chongqing Key Laboratory of Ophthalmology, Chongqing, 400016, P. R. China
- Chongqing Eye Institute, Chongqing, 400016, P. R. China
- Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, 400016, P. R. China
| | - Shengping Hou
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
- Chongqing Key Laboratory of Ophthalmology, Chongqing, 400016, P. R. China
- Chongqing Eye Institute, Chongqing, 400016, P. R. China
- Chongqing Branch (Municipality Division) of National Clinical Research Center for Ocular Diseases, Chongqing, 400016, P. R. China
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing, 100730, P. R. China
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30
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Cehajic-Kapetanovic J, Singh MS, Zrenner E, MacLaren RE. Bioengineering strategies for restoring vision. Nat Biomed Eng 2023; 7:387-404. [PMID: 35102278 DOI: 10.1038/s41551-021-00836-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 11/30/2021] [Indexed: 12/15/2022]
Abstract
Late-stage retinal degenerative disease involving photoreceptor loss can be treated by optogenetic therapy, cell transplantation and retinal prostheses. These approaches aim to restore light sensitivity to the retina as well as visual perception by integrating neuronal responses for transmission to the cortex. In age-related macular degeneration, some cell-based therapies also aim to restore photoreceptor-supporting tissue to prevent complete photoreceptor loss. In the earlier stages of degeneration, gene-replacement therapy could attenuate retinal-disease progression and reverse loss of function. And gene-editing strategies aim to correct the underlying genetic defects. In this Review, we highlight the most promising gene therapies, cell therapies and retinal prostheses for the treatment of retinal disease, discuss the benefits and drawbacks of each treatment strategy and the factors influencing whether functional tissue is reconstructed and repaired or replaced with an electronic device, and summarize upcoming technologies for enhancing the restoration of vision.
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Affiliation(s)
- Jasmina Cehajic-Kapetanovic
- Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, UK.
- Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
| | | | - Eberhart Zrenner
- Institute for Ophthalmic Research, Center for Ophthalmology, University of Tübingen, Tübingen, Germany
| | - Robert E MacLaren
- Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, UK
- Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
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31
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Eastlake K, Luis J, Wang W, Lamb W, Khaw PT, Limb GA. Transcriptomics of CD29 +/CD44 + cells isolated from hPSC retinal organoids reveals a single cell population with retinal progenitor and Müller glia characteristics. Sci Rep 2023; 13:5081. [PMID: 36977817 PMCID: PMC10050419 DOI: 10.1038/s41598-023-32058-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 03/21/2023] [Indexed: 03/30/2023] Open
Abstract
Müller glia play very important and diverse roles in retinal homeostasis and disease. Although much is known of the physiological and morphological properties of mammalian Müller glia, there is still the need to further understand the profile of these cells during human retinal development. Using human embryonic stem cell-derived retinal organoids, we investigated the transcriptomic profiles of CD29+/CD44+ cells isolated from early and late stages of organoid development. Data showed that these cells express classic markers of retinal progenitors and Müller glia, including NFIX, RAX, PAX6, VSX2, HES1, WNT2B, SOX, NR2F1/2, ASCL1 and VIM, as early as days 10-20 after initiation of retinal differentiation. Expression of genes upregulated in CD29+/CD44+ cells isolated at later stages of organoid development (days 50-90), including NEUROG1, VSX2 and ASCL1 were gradually increased as retinal organoid maturation progressed. Based on the current observations that CD24+/CD44+ cells share the characteristics of early and late-stage retinal progenitors as well as of mature Müller glia, we propose that these cells constitute a single cell population that upon exposure to developmental cues regulates its gene expression to adapt to functions exerted by Müller glia in the postnatal and mature retina.
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Affiliation(s)
- Karen Eastlake
- NIHR Biomedical Research Centre at Moorfields Eye Hospital, UCL Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, UK.
| | - Joshua Luis
- NIHR Biomedical Research Centre at Moorfields Eye Hospital, UCL Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, UK
| | - Weixin Wang
- NIHR Biomedical Research Centre at Moorfields Eye Hospital, UCL Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, UK
| | - William Lamb
- NIHR Biomedical Research Centre at Moorfields Eye Hospital, UCL Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, UK
| | - Peng T Khaw
- NIHR Biomedical Research Centre at Moorfields Eye Hospital, UCL Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, UK
| | - G Astrid Limb
- NIHR Biomedical Research Centre at Moorfields Eye Hospital, UCL Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, UK.
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32
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Agarwal D, Do H, Mazo KW, Chopra M, Wahlin KJ. Restoring vision and rebuilding the retina by Müller glial cell reprogramming. Stem Cell Res 2023; 66:103006. [PMID: 36563542 PMCID: PMC10783479 DOI: 10.1016/j.scr.2022.103006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 12/15/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022] Open
Abstract
Müller glia are non-neuronal support cells that play a vital role in the homeostasis of the eye. Their radial-oriented processes span the width of the retina and respond to injury through a cellular response that can be detrimental or protective depending on the context. In some species, protective responses include the expression of stem cell-like genes which help to fuel new neuron formation and even restoration of vision. In many lower vertebrates including fish and amphibians, this response is well documented, however, in mammals it is severely limited. The remarkable plasticity of cellular reprogramming in lower vertebrates has inspired studies in mammals for repairing the retina and restoring sight, and recent studies suggest that mammals are also capable of regeneration, albeit to a lesser degree. Endogenous regeneration, whereby new retinal neurons are created from existing support cells, offers an exciting alternative approach to existing tissue transplant, gene therapy, and neural prosthetic approaches being explored in parallel. This review will highlight the role of Müller glia during retinal injury and repair. In the end, prospects for advancing retinal regeneration research will be considered.
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Affiliation(s)
- Devansh Agarwal
- Department of Bioengineering, University of California, San Diego, United States; Department of Ophthalmology, University of California, San Diego, United States
| | - Hope Do
- Department of Ophthalmology, University of California, San Diego, United States; Department of Biological Sciences, University of California, San Diego, United States
| | - Kevin W Mazo
- Department of Ophthalmology, University of California, San Diego, United States; Department of Biological Sciences, University of California, San Diego, United States
| | - Manan Chopra
- Department of Ophthalmology, University of California, San Diego, United States; Department of Biological Sciences, University of California, San Diego, United States
| | - Karl J Wahlin
- Department of Ophthalmology, University of California, San Diego, United States.
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33
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Marchese NA, Ríos MN, Guido ME. Müller glial cell photosensitivity: a novel function bringing higher complexity to vertebrate retinal physiology. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY 2023. [DOI: 10.1016/j.jpap.2023.100162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
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34
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Bise T, Pfefferli C, Bonvin M, Taylor L, Lischer HEL, Bruggmann R, Jaźwińska A. The regeneration-responsive element careg monitors activation of Müller glia after MNU-induced damage of photoreceptors in the zebrafish retina. Front Mol Neurosci 2023; 16:1160707. [PMID: 37138703 PMCID: PMC10149768 DOI: 10.3389/fnmol.2023.1160707] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 03/27/2023] [Indexed: 05/05/2023] Open
Abstract
In contrast to mammals, zebrafish can regenerate their damaged photoreceptors. This capacity depends on the intrinsic plasticity of Müller glia (MG). Here, we identified that the transgenic reporter careg, a marker of regenerating fin and heart, also participates in retina restoration in zebrafish. After methylnitrosourea (MNU) treatment, the retina became deteriorated and contained damaged cell types including rods, UV-sensitive cones and the outer plexiform layer. This phenotype was associated with the induction of careg expression in a subset of MG until the reconstruction of the photoreceptor synaptic layer. Single-cell RNA sequencing (scRNAseq) analysis of regenerating retinas revealed a population of immature rods, defined by high expression of rhodopsin and the ciliogenesis gene meig1, but low expression of phototransduction genes. Furthermore, cones displayed deregulation of metabolic and visual perception genes in response to retina injury. Comparison between careg:EGFP expressing and non-expressing MG demonstrated that these two subpopulations are characterized by distinct molecular signatures, suggesting their heterogenous responsiveness to the regenerative program. Dynamics of ribosomal protein S6 phosphorylation showed that TOR signaling became progressively switched from MG to progenitors. Inhibition of TOR with rapamycin reduced the cell cycle activity, but neither affected careg:EGFP expression in MG, nor prevented restoration of the retina structure. This indicates that MG reprogramming, and progenitor cell proliferation might be regulated by distinct mechanisms. In conclusion, the careg reporter detects activated MG, and provides a common marker of regeneration-competent cells in diverse zebrafish organs, including the retina.
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Affiliation(s)
- Thomas Bise
- Department of Biology, University of Fribourg, Fribourg, Switzerland
| | | | - Marylène Bonvin
- Department of Biology, University of Fribourg, Fribourg, Switzerland
| | - Lea Taylor
- Interfaculty Bioinformatics Unit, University of Bern, Bern, Switzerland
- Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland
| | - Heidi E. L. Lischer
- Interfaculty Bioinformatics Unit, University of Bern, Bern, Switzerland
- Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland
| | - Rémy Bruggmann
- Interfaculty Bioinformatics Unit, University of Bern, Bern, Switzerland
- Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland
| | - Anna Jaźwińska
- Department of Biology, University of Fribourg, Fribourg, Switzerland
- *Correspondence: Anna Jaźwińska,
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35
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Miranda-Negrón Y, García-Arrarás JE. Radial glia and radial glia-like cells: Their role in neurogenesis and regeneration. Front Neurosci 2022; 16:1006037. [PMID: 36466166 PMCID: PMC9708897 DOI: 10.3389/fnins.2022.1006037] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/21/2022] [Indexed: 01/25/2024] Open
Abstract
Radial glia is a cell type traditionally associated with the developing nervous system, particularly with the formation of cortical layers in the mammalian brain. Nonetheless, some of these cells, or closely related types, called radial glia-like cells are found in adult central nervous system structures, functioning as neurogenic progenitors in normal homeostatic maintenance and in response to injury. The heterogeneity of radial glia-like cells is nowadays being probed with molecular tools, primarily by the expression of specific genes that define cell types. Similar markers have identified radial glia-like cells in the nervous system of non-vertebrate organisms. In this review, we focus on adult radial glia-like cells in neurogenic processes during homeostasis and in response to injury. We highlight our results using a non-vertebrate model system, the echinoderm Holothuria glaberrima where we have described a radial glia-like cell that plays a prominent role in the regeneration of the holothurian central nervous system.
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Affiliation(s)
| | - José E. García-Arrarás
- Department of Biology, College of Natural Sciences, University of Puerto Rico, San Juan, Puerto Rico
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36
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Age- and cell cycle-related expression patterns of transcription factors and cell cycle regulators in Müller glia. Sci Rep 2022; 12:19584. [PMID: 36379991 PMCID: PMC9666513 DOI: 10.1038/s41598-022-23855-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 11/07/2022] [Indexed: 11/16/2022] Open
Abstract
Mammalian Müller glia express transcription factors and cell cycle regulators essential for the function of retinal progenitors, indicating the latent neurogenic capacity; however, the role of these regulators remains unclear. To gain insights into the role of these regulators in Müller glia, we analyzed expression of transcription factors (Pax6, Vsx2 and Nfia) and cell cycle regulators (cyclin D1 and D3) in rodent Müller glia, focusing on their age- and cell cycle-related expression patterns. Expression of Pax6, Vsx2, Nfia and cyclin D3, but not cyclin D1, increased in Müller glia during development. Photoreceptor injury induced cell cycle-associated increase of Vsx2 and cyclin D1, but not Pax6, Nfia, and cyclin D3. In dissociated cultures, cell cycle-associated increase of Pax6 and Vsx2 was observed in Müller glia from P10 mice but not from P21 mice. Nfia levels were highly correlated with EdU incorporation suggesting their activation during S phase progression. Cyclin D1 and D3 were transiently upregulated in G1 phase but downregulated after S phase entry. Our findings revealed previously unknown links between cell cycle progression and regulator protein expression, which likely affect the cell fate decision of proliferating Müller glia.
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37
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Fitzpatrick MJ, Kerschensteiner D. Homeostatic plasticity in the retina. Prog Retin Eye Res 2022; 94:101131. [PMID: 36244950 DOI: 10.1016/j.preteyeres.2022.101131] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/25/2022] [Accepted: 09/28/2022] [Indexed: 02/07/2023]
Abstract
Vision begins in the retina, whose intricate neural circuits extract salient features of the environment from the light entering our eyes. Neurodegenerative diseases of the retina (e.g., inherited retinal degenerations, age-related macular degeneration, and glaucoma) impair vision and cause blindness in a growing number of people worldwide. Increasing evidence indicates that homeostatic plasticity (i.e., the drive of a neural system to stabilize its function) can, in principle, preserve retinal function in the face of major perturbations, including neurodegeneration. Here, we review the circumstances and events that trigger homeostatic plasticity in the retina during development, sensory experience, and disease. We discuss the diverse mechanisms that cooperate to compensate and the set points and outcomes that homeostatic retinal plasticity stabilizes. Finally, we summarize the opportunities and challenges for unlocking the therapeutic potential of homeostatic plasticity. Homeostatic plasticity is fundamental to understanding retinal development and function and could be an important tool in the fight to preserve and restore vision.
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38
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Sharma P, Ramachandran R. Retina regeneration: lessons from vertebrates. OXFORD OPEN NEUROSCIENCE 2022; 1:kvac012. [PMID: 38596712 PMCID: PMC10913848 DOI: 10.1093/oons/kvac012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 05/24/2022] [Accepted: 06/25/2022] [Indexed: 04/11/2024]
Abstract
Unlike mammals, vertebrates such as fishes and frogs exhibit remarkable tissue regeneration including the central nervous system. Retina being part of the central nervous system has attracted the interest of several research groups to explore its regenerative ability in different vertebrate models including mice. Fishes and frogs completely restore the size, shape and tissue structure of an injured retina. Several studies have unraveled molecular mechanisms underlying retina regeneration. In teleosts, soon after injury, the Müller glial cells of the retina reprogram to form a proliferating population of Müller glia-derived progenitor cells capable of differentiating into various neural cell types and Müller glia. In amphibians, the transdifferentiation of retinal pigment epithelium and differentiation of ciliary marginal zone cells contribute to retina regeneration. In chicks and mice, supplementation with external growth factors or genetic modifications cause a partial regenerative response in the damaged retina. The initiation of retina regeneration is achieved through sequential orchestration of gene expression through controlled modulations in the genetic and epigenetic landscape of the progenitor cells. Several developmental biology pathways are turned on during the Müller glia reprogramming, retinal pigment epithelium transdifferentiation and ciliary marginal zone differentiation. Further, several tumorigenic pathways and gene expression events also contribute to the complete regeneration cascade of events. In this review, we address the various retinal injury paradigms and subsequent gene expression events governed in different vertebrate species. Further, we compared how vertebrates such as teleost fishes and amphibians can achieve excellent regenerative responses in the retina compared with their mammalian counterparts.
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Affiliation(s)
- Poonam Sharma
- Department of Biological Sciences, Indian Institute of Science Education and Research, Mohali, Knowledge City, SAS Nagar, Sector 81, Manauli PO, 140306 Mohali, Punjab, India
| | - Rajesh Ramachandran
- Department of Biological Sciences, Indian Institute of Science Education and Research, Mohali, Knowledge City, SAS Nagar, Sector 81, Manauli PO, 140306 Mohali, Punjab, India
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39
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Todd L, Reh TA. Comparative Biology of Vertebrate Retinal Regeneration: Restoration of Vision through Cellular Reprogramming. Cold Spring Harb Perspect Biol 2022; 14:a040816. [PMID: 34580118 PMCID: PMC9248829 DOI: 10.1101/cshperspect.a040816] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The regenerative capacity of the vertebrate retina varies substantially across species. Whereas fish and amphibians can regenerate functional retina, mammals do not. In this perspective piece, we outline the various strategies nonmammalian vertebrates use to achieve functional regeneration of vision. We review key differences underlying the regenerative potential across species including the cellular source of postnatal progenitors, the diversity of cell fates regenerated, and the level of functional vision that can be achieved. Finally, we provide an outlook on the field of engineering the mammalian retina to replace neurons lost to injury or disease.
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Affiliation(s)
- Levi Todd
- Department of Biological Structure, University of Washington, Seattle, Washington 98195, USA
| | - Thomas A Reh
- Department of Biological Structure, University of Washington, Seattle, Washington 98195, USA
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40
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Ning R, Zheng D, Xie B, Gao G, Xu J, Xu P, Wang Y, Peng F, Jiang B, Ge J, Zhong X. Spatial and Temporal Development of Müller Glial Cells in hiPSC-Derived Retinal Organoids Facilitates the Cell Enrichment and Transcriptome Analysis. Front Cell Neurosci 2022; 16:820396. [PMID: 35663427 PMCID: PMC9160306 DOI: 10.3389/fncel.2022.820396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 04/19/2022] [Indexed: 11/18/2022] Open
Abstract
Müller glial cells (MGCs) play important roles in human retina during physiological and pathological conditions. However, the development process of human MGCs in vivo remains unclear, and how to obtain large numbers of human MGCs with high quality faces technical challenges, which hinder the further study and application of MGCs. Human induced pluripotent stem cell (hiPSC)-derived retinal organoids (ROs) with all retinal cell subtypes provide an unlimited cell resource and a platform for the studies of retinal development and disorders. This study explored the development of human MGCs in hiPSC-derived ROs and developed an approach to select and expand the induced MGCs (iMGCs). In ROs, retinal progenitor cells progressively differentiated into SOX9+ Ki67– MGC precursors during differentiation day (D) 60 to D90, while mature MGCs expressing markers CRALBP and GS gradually appeared since D120, which spanned the entire thickness of the neural retina layer. Cells isolated from ROs aged older than 120 days was an optimal source for the enrichment of iMGCs with high purity and expansion ability. They had typical features of human MGCs in morphological, structural, molecular and functional aspects, and could be passaged serially at least 10 times, yielding large numbers of cells in a short period. The transcriptome pattern of the expanded iMGCs was also revealed. This study firstly clarified the timecourse of human MGC development in the RO model, where the iMGCs could be enriched and expanded, paving the way for downstream investigation and application in MGC-related retinal disorders.
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Affiliation(s)
- Rong Ning
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Dandan Zheng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Bingbing Xie
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Guanjie Gao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Jinhai Xu
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Faculty of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Ping Xu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Yuan Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Fuhua Peng
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Bin Jiang
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Faculty of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Jian Ge
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Xiufeng Zhong
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
- *Correspondence: Xiufeng Zhong
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41
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Palazzo I, Todd LJ, Hoang TV, Reh TA, Blackshaw S, Fischer AJ. NFkB-signaling promotes glial reactivity and suppresses Müller glia-mediated neuron regeneration in the mammalian retina. Glia 2022; 70:1380-1401. [PMID: 35388544 DOI: 10.1002/glia.24181] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 03/28/2022] [Accepted: 03/29/2022] [Indexed: 12/25/2022]
Abstract
Müller glia (MG) in mammalian retinas are incapable of regenerating neurons after damage, whereas the MG in lower vertebrates regenerate functional neurons. Identification of cell signaling pathways and gene regulatory networks that regulate MG-mediated regeneration is key to harnessing the regenerative potential of MG. Here, we study how NFkB-signaling influences glial responses to damage and reprogramming of MG into neurons in the rodent retina. We find activation of NFkB and dynamic expression of NFkB-associated genes in MG after damage, however damage-induced NFkB activation is inhibited by microglia ablation. Knockout of NFkB in MG suppressed the accumulation of immune cells after damage. Inhibition of NFkB following NMDA-damage significantly enhanced the reprogramming of Ascl1-overexpressing MG into neuron-like cells. scRNA-seq of retinal glia following inhibition of NFkB reveals coordination with signaling via TGFβ2 and suppression of NFI and Id transcription factors. Inhibition of Smad3 signal transducer or Id transcription factors increased numbers of neuron-like cells produced by Ascl1-overexpressing MG. We conclude that NFkB is a key signaling hub that is activated in MG after damage, mediates the accumulation of immune cells, and suppresses the neurogenic potential of MG.
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Affiliation(s)
- Isabella Palazzo
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, Ohio, USA
| | - Levi J Todd
- Department of Biological Structure, College of Medicine, University of Washington, Seattle, Washington, USA
| | - Thanh V Hoang
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Thomas A Reh
- Department of Biological Structure, College of Medicine, University of Washington, Seattle, Washington, USA
| | - Seth Blackshaw
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Andy J Fischer
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, Ohio, USA
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42
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Gallo RA, Qureshi F, Strong TA, Lang SH, Pino KA, Dvoriantchikova G, Pelaez D. Derivation and Characterization of Murine and Amphibian Müller Glia Cell Lines. Transl Vis Sci Technol 2022; 11:4. [PMID: 35377941 PMCID: PMC8994200 DOI: 10.1167/tvst.11.4.4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Purpose Müller glia (MG) in the retina of Xenopus laevis (African clawed frog) reprogram to a transiently amplifying retinal progenitor state after an injury. These progenitors then give rise to new retinal neurons. In contrast, mammalian MG have a restricted neurogenic capacity and undergo reactive gliosis after injury. This study sought to establish MG cell lines from the regeneration-competent frog and the regeneration-deficient mouse. Methods MG were isolated from postnatal day 5 GLAST-CreERT; Rbfl/fl mice and from adult (3–5 years post-metamorphic) Xlaevis. Serial adherent subculture resulted in spontaneously immortalized cells and the establishment of two MG cell lines: murine retinal glia 17 (RG17) and Xenopus glia 69 (XG69). They were characterized for MG gene and protein expression by qPCR, immunostaining, and Western blot. Purinergic signaling was assessed with calcium imaging. Pharmacological perturbations with 2’-3’-O-(4-benzoylbenzoyl) adenosine 5’-triphosphate (BzATP) and KN-62 were performed on RG17 cells. Results RG17 and XG69 cells express several MG markers and retain purinergic signaling. Pharmacological perturbations of intracellular calcium responses with BzATP and KN-62 suggest that the ionotropic purinergic receptor P2X7 is present and functional in RG17 cells. Stimulation of XG69 cells with adenosine triphosphate–induced calcium responses in a dose-dependent manner. Conclusions We report the characterization of RG17 and XG69, two novel MG cell lines from species with significantly disparate retinal regenerative capabilities. Translational Relevance RG17 and XG69 cell line models will aid comparative studies between species endowed with varied regenerative capacity and will facilitate the development of new cell-based strategies for treating retinal degenerative diseases.
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Affiliation(s)
- Ryan A Gallo
- Dr. Nasser Ibrahim Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, USA.,Medical Scientist Training Program, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Farhan Qureshi
- Medical Scientist Training Program, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Thomas A Strong
- Dr. Nasser Ibrahim Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Steven H Lang
- Dr. Nasser Ibrahim Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Kevin A Pino
- Dr. Nasser Ibrahim Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Galina Dvoriantchikova
- Dr. Nasser Ibrahim Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Daniel Pelaez
- Dr. Nasser Ibrahim Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL, USA
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43
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Carpi-Santos R, de Melo Reis RA, Gomes FCA, Calaza KC. Contribution of Müller Cells in the Diabetic Retinopathy Development: Focus on Oxidative Stress and Inflammation. Antioxidants (Basel) 2022; 11:617. [PMID: 35453302 PMCID: PMC9027671 DOI: 10.3390/antiox11040617] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/01/2022] [Accepted: 03/15/2022] [Indexed: 01/27/2023] Open
Abstract
Diabetic retinopathy is a neurovascular complication of diabetes and the main cause of vision loss in adults. Glial cells have a key role in maintenance of central nervous system homeostasis. In the retina, the predominant element is the Müller cell, a specialized cell with radial morphology that spans all retinal layers and influences the function of the entire retinal circuitry. Müller cells provide metabolic support, regulation of extracellular composition, synaptic activity control, structural organization of the blood-retina barrier, antioxidant activity, and trophic support, among other roles. Therefore, impairments of Müller actions lead to retinal malfunctions. Accordingly, increasing evidence indicates that Müller cells are affected in diabetic retinopathy and may contribute to the severity of the disease. Here, we will survey recently described alterations in Müller cell functions and cellular events that contribute to diabetic retinopathy, especially related to oxidative stress and inflammation. This review sheds light on Müller cells as potential therapeutic targets of this disease.
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Affiliation(s)
- Raul Carpi-Santos
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil; (R.C.-S.); (F.C.A.G.)
| | - Ricardo A. de Melo Reis
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil;
| | - Flávia Carvalho Alcantara Gomes
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil; (R.C.-S.); (F.C.A.G.)
| | - Karin C. Calaza
- Instituto de Biologia, Departamento de Neurobiologia, Universidade Federal Fluminense, Niteroi 24210-201, RJ, Brazil
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Pereiro X, Beriain S, Rodriguez L, Roiz-Valle D, Ruzafa N, Vecino E. Characteristics of Whale Müller Glia in Primary and Immortalized Cultures. Front Neurosci 2022; 16:854278. [PMID: 35360150 PMCID: PMC8964101 DOI: 10.3389/fnins.2022.854278] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 02/22/2022] [Indexed: 11/16/2022] Open
Abstract
Müller cells are the principal glial cells in the retina and they assume many of the functions carried out by astrocytes, oligodendrocytes and ependymal cells in other regions of the central nervous system. Müller cells express growth factors, neurotransmitter transporters and antioxidant agents that could fulfill important roles in preventing excitotoxic damage to retinal neurons. Vertebrate Müller cells are well-defined cells, characterized by a common set of features throughout the phylum. Nevertheless, several major differences have been observed among the Müller cells in distinct vertebrates, such as neurogenesis, the capacity to reprogram fish Müller glia to neurons. Here, the Müller glia of the largest adult mammal in the world, the whale, have been analyzed, and given the difficulties in obtaining cetacean cells for study, these whale glia were analyzed both in primary cultures and as immortalized whale Müller cells. After isolating the retina from the eye of a beached sei whale (Balaenoptera borealis), primary Müller cell cultures were established and once the cultures reached confluence, half of the cultures were immortalized with the simian virus 40 (SV40) large T-antigen commonly used to immortalize human cell lines. The primary cell cultures were grown until cells reached senescence. Expression of the principal molecular markers of Müller cells (GFAP, Vimentin and Glutamine synthetase) was studied in both primary and immortalized cells at each culture passage. Proliferation kinetics of the cells were analyzed by time-lapse microscopy: the time between divisions, the time that cells take to divide, and the proportion of dividing cells in the same field. The karyotypes of the primary and immortalized whale Müller cells were also characterized. Our results shown that W21M proliferate more rapidly and they have a stable karyotype. W21M cells display a heterogeneous cell morphology, less motility and a distinctive expression of some typical molecular markers of Müller cells, with an increase in dedifferentiation markers like α-SMA and β-III tubulin, while they preserve their GS expression depending on the culture passage. Here we also discuss the possible influence of the animal's age and size on these cells, and on their senescence.
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Affiliation(s)
- Xandra Pereiro
- Experimental Ophthalmo-Biology Group, Department of Cell Biology and Histology, University of Basque Country UPV/EHU, Leioa, Spain
- Begiker-Ophthalmology Research Group, BioCruces Health Research Institute, Cruces Hospital, Barakaldo, Spain
| | - Sandra Beriain
- Experimental Ophthalmo-Biology Group, Department of Cell Biology and Histology, University of Basque Country UPV/EHU, Leioa, Spain
| | - Lara Rodriguez
- Experimental Ophthalmo-Biology Group, Department of Cell Biology and Histology, University of Basque Country UPV/EHU, Leioa, Spain
| | - David Roiz-Valle
- Department of Biochemistry and Molecular Biology, University Institute of Oncology (IUOPA), University of Oviedo, Oviedo, Spain
| | - Noelia Ruzafa
- Experimental Ophthalmo-Biology Group, Department of Cell Biology and Histology, University of Basque Country UPV/EHU, Leioa, Spain
- Begiker-Ophthalmology Research Group, BioCruces Health Research Institute, Cruces Hospital, Barakaldo, Spain
| | - Elena Vecino
- Experimental Ophthalmo-Biology Group, Department of Cell Biology and Histology, University of Basque Country UPV/EHU, Leioa, Spain
- Begiker-Ophthalmology Research Group, BioCruces Health Research Institute, Cruces Hospital, Barakaldo, Spain
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45
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Campbell WA, Tangeman A, El-Hodiri HM, Hawthorn EC, Hathoot M, Blum S, Hoang T, Blackshaw S, Fischer AJ. Fatty acid-binding proteins and fatty acid synthase influence glial reactivity and promote the formation of Müller glia-derived progenitor cells in the chick retina. Development 2022; 149:274285. [PMID: 35132991 PMCID: PMC8959147 DOI: 10.1242/dev.200127] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 01/18/2022] [Indexed: 11/20/2022]
Abstract
A recent comparative transcriptomic study of Müller glia (MG) in vertebrate retinas revealed that fatty acid binding proteins (FABPs) are among the most highly expressed genes in chick ( Hoang et al., 2020). Here, we investigate how FABPs and fatty acid synthase (FASN) influence glial cells in the chick retina. During development, FABP7 is highly expressed by retinal progenitor cells and maturing MG, whereas FABP5 is upregulated in maturing MG. PMP2 (FABP8) is expressed by oligodendrocytes and FABP5 is expressed by non-astrocytic inner retinal glial cells, and both of these FABPs are upregulated by activated MG. In addition to suppressing the formation of Müller glia-derived progenitor cells (MGPCs), we find that FABP-inhibition suppresses the proliferation of microglia. FABP-inhibition induces distinct changes in single cell transcriptomic profiles, indicating transitions of MG from resting to reactive states and suppressed MGPC formation, with upregulation of gene modules for gliogenesis and decreases in neurogenesis. FASN-inhibition increases the proliferation of microglia and suppresses the formation of MGPCs. We conclude that fatty acid metabolism and cell signaling involving fatty acids are important in regulating the reactivity and dedifferentiation of MG, and the proliferation of microglia and MGPCs.
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Affiliation(s)
- Warren A Campbell
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Allen Tangeman
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Heithem M El-Hodiri
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Evan C Hawthorn
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Maddie Hathoot
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Sydney Blum
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Thanh Hoang
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Seth Blackshaw
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Andy J Fischer
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
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Zibetti C. Deciphering the Retinal Epigenome during Development, Disease and Reprogramming: Advancements, Challenges and Perspectives. Cells 2022; 11:cells11050806. [PMID: 35269428 PMCID: PMC8908986 DOI: 10.3390/cells11050806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 02/15/2022] [Accepted: 02/18/2022] [Indexed: 02/01/2023] Open
Abstract
Retinal neurogenesis is driven by concerted actions of transcription factors, some of which are expressed in a continuum and across several cell subtypes throughout development. While seemingly redundant, many factors diversify their regulatory outcome on gene expression, by coordinating variations in chromatin landscapes to drive divergent retinal specification programs. Recent studies have furthered the understanding of the epigenetic contribution to the progression of age-related macular degeneration, a leading cause of blindness in the elderly. The knowledge of the epigenomic mechanisms that control the acquisition and stabilization of retinal cell fates and are evoked upon damage, holds the potential for the treatment of retinal degeneration. Herein, this review presents the state-of-the-art approaches to investigate the retinal epigenome during development, disease, and reprogramming. A pipeline is then reviewed to functionally interrogate the epigenetic and transcriptional networks underlying cell fate specification, relying on a truly unbiased screening of open chromatin states. The related work proposes an inferential model to identify gene regulatory networks, features the first footprinting analysis and the first tentative, systematic query of candidate pioneer factors in the retina ever conducted in any model organism, leading to the identification of previously uncharacterized master regulators of retinal cell identity, such as the nuclear factor I, NFI. This pipeline is virtually applicable to the study of genetic programs and candidate pioneer factors in any developmental context. Finally, challenges and limitations intrinsic to the current next-generation sequencing techniques are discussed, as well as recent advances in super-resolution imaging, enabling spatio-temporal resolution of the genome.
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Affiliation(s)
- Cristina Zibetti
- Department of Ophthalmology, Institute of Clinical Medicine, University of Oslo, Kirkeveien 166, Building 36, 0455 Oslo, Norway
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47
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Blackshaw S. Why Has the Ability to Regenerate Following CNS Injury Been Repeatedly Lost Over the Course of Evolution? Front Neurosci 2022; 16:831062. [PMID: 35185460 PMCID: PMC8854365 DOI: 10.3389/fnins.2022.831062] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 01/13/2022] [Indexed: 12/30/2022] Open
Abstract
While many vertebrates can regenerate both damaged neurons and severed axons in the central nervous system (CNS) following injury, others, including all birds and mammals, have lost this ability for reasons that are still unclear. The repeated evolutionary loss of regenerative competence seems counterintuitive, and any explanation must account for the fact that regenerative competence is lost in both cold-blooded and all warm-blooded clades, that both injury-induced neurogenesis and axonal regeneration tend to be lost in tandem, and that mammals have evolved dedicated gene regulatory networks to inhibit injury-induced glia-to-neuron reprogramming. Here, different hypotheses that have been proposed to account for evolutionary loss of regenerative competence are discussed in the light of new insights obtained into molecular mechanisms that control regeneration in the central nervous system. These include pleiotropic effects of continuous growth, enhanced thyroid hormone signaling, prevention of neoplasia, and improved memory consolidation. Recent evidence suggests that the most compelling hypothesis, however, may be selection for greater resistance to the spread of intra-CNS infections, which has led to both enhanced reactive gliosis and a loss of injury-induced neurogenesis and axonal regeneration. Means of testing these hypotheses, and additional data that are urgently needed to better understand the evolutionary pressures and mechanisms driving loss of regenerative competence, are also discussed.
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Affiliation(s)
- Seth Blackshaw
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- *Correspondence: Seth Blackshaw,
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48
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Brunet AA, Harvey AR, Carvalho LS. Primary and Secondary Cone Cell Death Mechanisms in Inherited Retinal Diseases and Potential Treatment Options. Int J Mol Sci 2022; 23:ijms23020726. [PMID: 35054919 PMCID: PMC8775779 DOI: 10.3390/ijms23020726] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 01/05/2022] [Accepted: 01/05/2022] [Indexed: 12/13/2022] Open
Abstract
Inherited retinal diseases (IRDs) are a leading cause of blindness. To date, 260 disease-causing genes have been identified, but there is currently a lack of available and effective treatment options. Cone photoreceptors are responsible for daylight vision but are highly susceptible to disease progression, the loss of cone-mediated vision having the highest impact on the quality of life of IRD patients. Cone degeneration can occur either directly via mutations in cone-specific genes (primary cone death), or indirectly via the primary degeneration of rods followed by subsequent degeneration of cones (secondary cone death). How cones degenerate as a result of pathological mutations remains unclear, hindering the development of effective therapies for IRDs. This review aims to highlight similarities and differences between primary and secondary cone cell death in inherited retinal diseases in order to better define cone death mechanisms and further identify potential treatment options.
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Affiliation(s)
- Alicia A. Brunet
- Centre for Ophthalmology and Visual Sciences, The University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009, Australia;
- Lions Eye Institute Ltd., 2 Verdun St, Nedlands, WA 6009, Australia
- Correspondence: ; Tel.: +61-423-359-714
| | - Alan R. Harvey
- School of Human Sciences, The University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009, Australia;
- Perron Institute for Neurological and Translational Science, 8 Verdun St, Nedlands, WA 6009, Australia
| | - Livia S. Carvalho
- Centre for Ophthalmology and Visual Sciences, The University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009, Australia;
- Lions Eye Institute Ltd., 2 Verdun St, Nedlands, WA 6009, Australia
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Bulirsch LM, Loeffler KU, Holz FG, Koinzer S, Nadal J, Müller AM, Herwig-Carl MC. Spatial and temporal immunoreaction of nestin, CD44, collagen IX and GFAP in human retinal Müller cells in the developing fetal eye. Exp Eye Res 2022; 217:108958. [DOI: 10.1016/j.exer.2022.108958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 01/17/2022] [Accepted: 01/18/2022] [Indexed: 11/30/2022]
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German OL, Vallese-Maurizi H, Soto TB, Rotstein NP, Politi LE. Retina stem cells, hopes and obstacles. World J Stem Cells 2021; 13:1446-1479. [PMID: 34786153 PMCID: PMC8567457 DOI: 10.4252/wjsc.v13.i10.1446] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 07/14/2021] [Accepted: 09/17/2021] [Indexed: 02/07/2023] Open
Abstract
Retinal degeneration is a major contributor to visual dysfunction worldwide. Although it comprises several eye diseases, loss of retinal pigment epithelial (RPE) and photoreceptor cells are the major contributors to their pathogenesis. Early therapies included diverse treatments, such as provision of anti-vascular endothelial growth factor and many survival and trophic factors that, in some cases, slow down the progression of the degeneration, but do not effectively prevent it. The finding of stem cells (SC) in the eye has led to the proposal of cell replacement strategies for retina degeneration. Therapies using different types of SC, such as retinal progenitor cells (RPCs), embryonic SC, pluripotent SCs (PSCs), induced PSCs (iPSCs), and mesenchymal stromal cells, capable of self-renewal and of differentiating into multiple cell types, have gained ample support. Numerous preclinical studies have assessed transplantation of SC in animal models, with encouraging results. The aim of this work is to revise the different preclinical and clinical approaches, analyzing the SC type used, their efficacy, safety, cell attachment and integration, absence of tumor formation and immunorejection, in order to establish which were the most relevant and successful. In addition, we examine the questions and concerns still open in the field. The data demonstrate the existence of two main approaches, aimed at replacing either RPE cells or photoreceptors. Emerging evidence suggests that RPCs and iPSC are the best candidates, presenting no ethical concerns and a low risk of immunorejection. Clinical trials have already supported the safety and efficacy of SC treatments. Serious concerns are pending, such as the risk of tumor formation, lack of attachment or integration of transplanted cells into host retinas, immunorejection, cell death, and also ethical. However, the amazing progress in the field in the last few years makes it possible to envisage safe and effective treatments to restore vision loss in a near future.
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Affiliation(s)
- Olga L German
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, Bahia blanca 8000, Buenos Aires, Argentina
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Harmonie Vallese-Maurizi
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, Bahia blanca 8000, Buenos Aires, Argentina
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Tamara B Soto
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Nora P Rotstein
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, Bahia blanca 8000, Buenos Aires, Argentina
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Luis Enrique Politi
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
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