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Jia K, Cheng B, Huang L, Xu J, Liu F, Liao X, Liao K, Lu H. Activation of prep expression by Tet2 promotes the proliferation of bipotential progenitor cells during liver regeneration. Development 2025; 152:DEV204339. [PMID: 39976298 DOI: 10.1242/dev.204339] [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: 08/20/2024] [Accepted: 01/30/2025] [Indexed: 02/21/2025]
Abstract
Biliary epithelial cell (BEC)-derived liver regeneration in zebrafish exhibits similarities to liver regeneration in chronic liver injury. However, the underlying mechanisms remain poorly understood. Here, we identified a serine peptidase called prolyl endopeptidase (Prep) as an indispensable factor during the BEC-derived liver regeneration process. prep was significantly upregulated and enriched in bipotential progenitor cells (BP-PCs). Through gain- and loss-of-function assays, prep was found to potently accelerate liver regeneration and drastically increase the proliferation of BP-PCs. Mechanistically, prep expression was directly regulated by ten-eleven translocation 2 (Tet2)-mediated DNA demethylation. More strikingly, Tet2 regulated prep expression by directly interacting and reducing the methylation of CpG sites in the prep promoter. Subsequently, Prep activated the PI3K-AKT-mTOR signaling pathway to regulate liver regeneration. Therefore, our study revealed the role and mechanism of Tet2-mediated DNA demethylation-associated upregulation of prep in the proliferation of BP-PCs during liver regeneration. These results identify promising targets for stimulating regeneration following chronic liver injury.
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Affiliation(s)
- Kun Jia
- Center for Clinical Medicine Research , First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, Jiangxi, China
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs , Jinggangshan University, Ji'an 343009, China
- School of Marine Science , Ningbo University, Ningbo 315832, China
| | - Bo Cheng
- Ganzhou Key Laboratory for Drug Screening and Discovery, School of Geography and Environmental Engineering , Gannan Normal University, Ganzhou 341000, Jiangxi, China
| | - Lirong Huang
- Ganzhou Key Laboratory for Drug Screening and Discovery, School of Geography and Environmental Engineering , Gannan Normal University, Ganzhou 341000, Jiangxi, China
| | - Jiaxin Xu
- Ganzhou Key Laboratory for Drug Screening and Discovery, School of Geography and Environmental Engineering , Gannan Normal University, Ganzhou 341000, Jiangxi, China
| | - Fasheng Liu
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs , Jinggangshan University, Ji'an 343009, China
| | - Xinjun Liao
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs , Jinggangshan University, Ji'an 343009, China
| | - Kai Liao
- School of Marine Science , Ningbo University, Ningbo 315832, China
| | - Huiqiang Lu
- Center for Clinical Medicine Research , First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, Jiangxi, China
- Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs , Jinggangshan University, Ji'an 343009, China
- Ganzhou Key Laboratory for Drug Screening and Discovery, School of Geography and Environmental Engineering , Gannan Normal University, Ganzhou 341000, Jiangxi, China
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Wu J, Xu M, Qin C, Guo Y, Wang Y, Wang Z, Li Q. Joint profiling of DNA methylomics and transcriptomic reveals roles of demethylation in regeneration of coelomocytes after evisceration in sea cucumber Apostichopus japonicus. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART D, GENOMICS & PROTEOMICS 2025; 55:101456. [PMID: 40015132 DOI: 10.1016/j.cbd.2025.101456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 02/21/2025] [Accepted: 02/22/2025] [Indexed: 03/01/2025]
Abstract
Generally, there is a large number of deaths for sea cucumber along with evisceration after which a weakly immune state occurs because of a poor resistance against a variety of pathogens and environmental stress. The regeneration of coelomocytes plays an important role in the remodeling of the immune defense system after evisceration with the decrease of methylation modification. In this study, the whole DNA methylation of coelomocytes is detected post evisceration in Apostichopus japonicus to explore the process of cell regeneration. Our results found that total methylation level reached a lowest point at 12 h (9.8 %), which was followed by increased at 24 h. The transcriptomic and DNA methylomic analysis indicated a total of 215 genes were identified by selecting the significant hypomethylation within the 2-kilobase region of the transcriptional start site upstream. The KEGG pathway enrichment analyses of the 215 genes showed that signal transduction, signaling molecules and interaction were significantly enriched. The genes were enriched in the top 20 signaling pathway, such as IGF1R, Notch2 and HSPA1s. Taken together, this study provides new clues for deciphering the coelomocytes regeneration after evisceration of A. japonicus by DNA demethylation.
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Affiliation(s)
- Jiong Wu
- Tianjin Key Lab of Aqua-ecology and Aquaculture, Fisheries College, Tianjin Agricultural University, Tianjin 300384, China; Key Laboratory of Efficient Utilization and Processing of Marine Fishery Resources of Hainan Province, Sanya Tropical Fisheries Research Institute, Sanya 572426, China
| | - Mingmei Xu
- Tianjin Key Lab of Aqua-ecology and Aquaculture, Fisheries College, Tianjin Agricultural University, Tianjin 300384, China
| | - Chuanxin Qin
- Key Laboratory of Efficient Utilization and Processing of Marine Fishery Resources of Hainan Province, Sanya Tropical Fisheries Research Institute, Sanya 572426, China
| | - Yu Guo
- Key Laboratory of Efficient Utilization and Processing of Marine Fishery Resources of Hainan Province, Sanya Tropical Fisheries Research Institute, Sanya 572426, China
| | - Yinan Wang
- Tianjin Key Lab of Aqua-ecology and Aquaculture, Fisheries College, Tianjin Agricultural University, Tianjin 300384, China
| | - Zhenhui Wang
- Yancheng Institute of Technology Department: College of Marine and Bioengineering, Yancheng 224051, China.
| | - Qiang Li
- Tianjin Key Lab of Aqua-ecology and Aquaculture, Fisheries College, Tianjin Agricultural University, Tianjin 300384, China.
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Gupta S, Hui SP. Epigenetic Cross-Talk Between Sirt1 and Dnmt1 Promotes Axonal Regeneration After Spinal Cord Injury in Zebrafish. Mol Neurobiol 2025; 62:2396-2419. [PMID: 39110393 DOI: 10.1007/s12035-024-04408-w] [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: 04/24/2024] [Accepted: 07/28/2024] [Indexed: 01/28/2025]
Abstract
Though spinal cord injury (SCI) causes irreversible sensory and motor impairments in human, adult zebrafish retain the potent regenerative capacity by injury-induced proliferation of central nervous system (CNS)-resident progenitor cells to develop new functional neurons at the lesion site. The hallmark of SCI in zebrafish lies in a series of changes in the epigenetic landscape, specifically DNA methylation and histone modifications. Decoding the post-SCI epigenetic modifications is therefore critical for the development of therapeutic remedies that boost SCI recovery process. Here, we have studied on Sirtuin1 (Sirt1), a non-classical histone deacetylase that potentially plays a critical role in neural progenitor cells (NPC) proliferation and axonal regrowth following SCI in zebrafish. We investigated the role of Sirt1 in NPC proliferation and axonal regrowth in response to injury in the regenerating spinal cord and found that Sirt1 is involved in the induction of NPC proliferation along with glial bridging during spinal cord regeneration. We also demonstrate that Sirt1 plays a pivotal role in regulating the HIPPO pathway through deacetylation-mediated inactivation of Dnmt1 and subsequent hypomethylation of yap1 promoter, leading to the induction of ctgfa expression, which drives the NPC proliferation and axonal regrowth to complete the regenerative process. In conclusion, our study reveals a novel cross-talk between two important epigenetic effectors, Sirt1 and Dnmt1, in the context of spinal cord regeneration, establishing a previously undisclosed relation between Sirt1 and Yap1 which provides a deeper understanding of the underlying mechanisms governing injury-induced NPC proliferation and axonal regrowth. Therefore, we have identified Sirt1 as a novel, major epigenetic regulator of spinal cord regeneration by modulating the HIPPO pathway in zebrafish.
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Affiliation(s)
- Samudra Gupta
- S. N. Pradhan Centre for Neurosciences, University of Calcutta, 35, Ballygunge Circular Road, Kolkata, 700019, India
| | - Subhra Prakash Hui
- S. N. Pradhan Centre for Neurosciences, University of Calcutta, 35, Ballygunge Circular Road, Kolkata, 700019, India.
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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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5
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La Pietra A, Bianchi AR, Capriello T, Mobilio T, Guagliardi A, De Maio A, Ferrandino I. Regeneration of zebrafish retina following toxic injury. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2024; 112:104582. [PMID: 39481820 DOI: 10.1016/j.etap.2024.104582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 10/10/2024] [Accepted: 10/28/2024] [Indexed: 11/03/2024]
Abstract
The structure of the zebrafish retina appears to be very similar to that of mammals, that is why it is used as a model for studying the eye. Indeed, the zebrafish retina can regenerate itself through mechanisms of Müller cell reprogramming. In this research, adult zebrafish were exposed to aluminum to cause damage in the retina and thus evaluate the regenerative capacity of the damaged tissue. Histological and histochemical analyses assessed the retinal structure and the neurodegenerative process, respectively. An expression analysis of PARPs was carried out to verify whether a potential oxidative DNA damage happens. In addition, some genes involved in the regeneration process (pax6a, pax2a, ngn1, and notch1a) were analyzed. The data confirmed the toxicity of aluminum which caused retinal neurodegeneration, but also highlighted the ability of zebrafish to regenerate the retinal structure, repairing the damage and confirming its use as a good model for translational studies.
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Affiliation(s)
- Alessandra La Pietra
- Department of Biology, University of Naples Federico II, Via Cinthia 21, Naples 80126, Italy.
| | - Anna Rita Bianchi
- Department of Biology, University of Naples Federico II, Via Cinthia 21, Naples 80126, Italy.
| | - Teresa Capriello
- Department of Biology, University of Naples Federico II, Via Cinthia 21, Naples 80126, Italy.
| | - Teresa Mobilio
- Department of Biology, University of Naples Federico II, Via Cinthia 21, Naples 80126, Italy.
| | - Annamaria Guagliardi
- Department of Biology, University of Naples Federico II, Via Cinthia 21, Naples 80126, Italy.
| | - Anna De Maio
- Department of Biology, University of Naples Federico II, Via Cinthia 21, Naples 80126, Italy.
| | - Ida Ferrandino
- Department of Biology, University of Naples Federico II, Via Cinthia 21, Naples 80126, Italy.
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6
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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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7
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Liu H, Lu S, Chen M, Gao N, Yang Y, Hu H, Ren Q, Liu X, Chen H, Zhu Q, Li S, Su J. Towards Stem/Progenitor Cell-Based Therapies for Retinal Degeneration. Stem Cell Rev Rep 2024; 20:1459-1479. [PMID: 38809490 DOI: 10.1007/s12015-024-10740-4] [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] [Accepted: 05/21/2024] [Indexed: 05/30/2024]
Abstract
Retinal degeneration (RD) is a leading cause of blindness worldwide and includes conditions such as retinitis pigmentosa (RP), age-related macular degeneration (AMD), and Stargardt's disease (STGD). These diseases result in the permanent loss of vision due to the progressive and irreversible degeneration of retinal cells, including photoreceptors (PR) and the retinal pigment epithelium (RPE). The adult human retina has limited abilities to regenerate and repair itself, making it challenging to achieve complete self-replenishment and functional repair of retinal cells. Currently, there is no effective clinical treatment for RD. Stem cell therapy, which involves transplanting exogenous stem cells such as retinal progenitor cells (RPCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and mesenchymal stem cells (MSCs), or activating endogenous stem cells like Müller Glia (MG) cells, holds great promise for regenerating and repairing retinal cells in the treatment of RD. Several preclinical and clinical studies have shown the potential of stem cell-based therapies for RD. However, the clinical translation of these therapies for the reconstruction of substantial vision still faces significant challenges. This review provides a comprehensive overview of stem/progenitor cell-based therapy strategies for RD, summarizes recent advances in preclinical studies and clinical trials, and highlights the major challenges in using stem/progenitor cell-based therapies for RD.
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Affiliation(s)
- Hui Liu
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Shuaiyan Lu
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Ming Chen
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Na Gao
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Yuhe Yang
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Huijuan Hu
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Qing Ren
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Xiaoyu Liu
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Hongxu Chen
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Qunyan Zhu
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, 325011, China
| | - Shasha Li
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, 325001, China.
| | - Jianzhong Su
- National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, 325011, China.
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, 325001, China.
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8
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Lee MS, Jui J, Sahu A, Goldman D. Mycb and Mych stimulate Müller glial cell reprogramming and proliferation in the uninjured and injured zebrafish retina. Development 2024; 151:dev203062. [PMID: 38984586 PMCID: PMC11369687 DOI: 10.1242/dev.203062] [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: 05/17/2024] [Accepted: 06/26/2024] [Indexed: 07/11/2024]
Abstract
In the injured zebrafish retina, Müller glial cells (MG) reprogram to adopt retinal stem cell properties and regenerate damaged neurons. The strongest zebrafish reprogramming factors might be good candidates for stimulating a similar regenerative response by mammalian MG. Myc proteins are potent reprogramming factors that can stimulate cellular plasticity in differentiated cells; however, their role in MG reprogramming and retina regeneration remains poorly explored. Here, we report that retinal injury stimulates mycb and mych expression and that, although both Mycb and Mych stimulate MG reprogramming and proliferation, only Mych enhances retinal neuron apoptosis. RNA-sequencing analysis of wild-type, mychmut and mycbmut fish revealed that Mycb and Mych regulate ∼40% and ∼16%, respectively, of the genes contributing to the regeneration-associated transcriptome of MG. Of these genes, those that are induced are biased towards regulation of ribosome biogenesis, protein synthesis, DNA synthesis, and cell division, which are the top cellular processes affected by retinal injury, suggesting that Mycb and Mych are potent MG reprogramming factors. Consistent with this, forced expression of either of these proteins is sufficient to stimulate MG proliferation in the uninjured retina.
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Affiliation(s)
- Mi-Sun Lee
- Michigan Neuroscience Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jonathan Jui
- Michigan Neuroscience Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
| | - Aresh Sahu
- Michigan Neuroscience Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
| | - Daniel Goldman
- Michigan Neuroscience Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
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Kolli RT, Glenn TC, Bringolf RB, Henderson M, Cummings BS, Kenneke JF. Changes in CpG Methylation of the Vitellogenin 1 Promoter in Adult Male Zebrafish after Exposure to 17α-Ethynylestradiol. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY 2024; 43:1547-1556. [PMID: 38785270 DOI: 10.1002/etc.5879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/17/2023] [Accepted: 03/28/2024] [Indexed: 05/25/2024]
Abstract
Numerous pharmaceutical and industrial chemicals are classified as endocrine-disrupting chemicals (EDCs) that interfere with hormonal homeostasis, leading to developmental disorders and other pathologies. The synthetic estrogen 17α-ethynylestradiol (EE2) is used in oral contraceptives and other hormone therapies. EE2 and other estrogens are inadvertently introduced into aquatic environments through municipal wastewater and agricultural effluents. Exposure of male fish to estrogens increases expression of the egg yolk precursor protein vitellogenin (Vtg), which is used as a molecular marker of exposure to estrogenic EDCs. The mechanisms behind Vtg induction are not fully known, and we hypothesized that it is regulated via DNA methylation. Adult zebrafish were exposed to either dimethyl sulfoxide or 20 ng/L EE2 for 14 days. Messenger RNA (mRNA) expression and DNA methylation were assessed in male zebrafish livers at 0, 0.25, 0.5, 1, 4, 7, and 14 days of exposure; and those of females were assessed at 13 days (n ≥ 4/group/time point). To test the persistence of any changes, we included a recovery group that received EE2 for 7 days and did not receive any for the following 7 days, in the total 14-day study. Methylation of DNA at the vtg1 promoter was assessed with targeted gene bisulfite sequencing in livers of adult male and female zebrafish. A significant increase in vtg1 mRNA was observed in the EE2-exposed male fish as early as 6 h. Interestingly, DNA methylation changes were observed at 4 days. Decreases in the overall methylation of the vtg1 promoter in exposed males resulted in levels comparable to those in female controls, suggesting feminization. Importantly, DNA methylation levels in males remained significantly impacted after 7 days post-EE2 removal, unlike mRNA levels. These data identify an epigenetic mark of feminization that may serve as an indicator of not only estrogenic exposure but also previous exposure to EE2. Environ Toxicol Chem 2024;43:1547-1556. © 2024 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
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Affiliation(s)
- Ramya T Kolli
- Interdisciplinary Toxicology Program, University of Georgia, Athens, Georgia, USA
- Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia, USA
- Student Services Authority, Athens, Georgia, USA
| | - Travis C Glenn
- Interdisciplinary Toxicology Program, University of Georgia, Athens, Georgia, USA
- Environmental Health Science, University of Georgia, Athens, Georgia, USA
| | - Robert B Bringolf
- Interdisciplinary Toxicology Program, University of Georgia, Athens, Georgia, USA
- Warnell School of Forestry and Natural Resources, University of Georgia, Athens, Georgia, USA
| | - Matthew Henderson
- Center for Environmental Measurement and Modeling, Office of Research and Development, US Environmental Protection Agency, Athens, Georgia
| | - Brian S Cummings
- Interdisciplinary Toxicology Program, University of Georgia, Athens, Georgia, USA
- Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia, USA
- Pharmaceutical Sciences, Wayne State University, Detroit, Michigan, USA
| | - John F Kenneke
- Center for Computational Toxicology and Exposure, Office of Research and Development, US Environmental Protection Agency, Athens, Georgia
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10
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Lorenzo JP, Molla L, Amro EM, Ibarra IL, Ruf S, Neber C, Gkougkousis C, Ridani J, Subramani PG, Boulais J, Harjanto D, Vonica A, Di Noia JM, Dieterich C, Zaugg JB, Papavasiliou FN. APOBEC2 safeguards skeletal muscle cell fate through binding chromatin and regulating transcription of non-muscle genes during myoblast differentiation. Proc Natl Acad Sci U S A 2024; 121:e2312330121. [PMID: 38625936 PMCID: PMC11047093 DOI: 10.1073/pnas.2312330121] [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: 07/25/2023] [Accepted: 03/07/2024] [Indexed: 04/18/2024] Open
Abstract
The apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide (APOBEC) family is composed of nucleic acid editors with roles ranging from antibody diversification to RNA editing. APOBEC2, a member of this family with an evolutionarily conserved nucleic acid-binding cytidine deaminase domain, has neither an established substrate nor function. Using a cellular model of muscle differentiation where APOBEC2 is inducibly expressed, we confirmed that APOBEC2 does not have the attributed molecular functions of the APOBEC family, such as RNA editing, DNA demethylation, and DNA mutation. Instead, we found that during muscle differentiation APOBEC2 occupied a specific motif within promoter regions; its removal from those regions resulted in transcriptional changes. Mechanistically, these changes reflect the direct interaction of APOBEC2 with histone deacetylase (HDAC) transcriptional corepressor complexes. We also found that APOBEC2 could bind DNA directly, in a sequence-specific fashion, suggesting that it functions as a recruiter of HDAC to specific genes whose promoters it occupies. These genes are normally suppressed during muscle cell differentiation, and their suppression may contribute to the safeguarding of muscle cell fate. Altogether, our results reveal a unique role for APOBEC2 within the APOBEC family.
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Affiliation(s)
- J. Paulo Lorenzo
- Division of Immune Diversity, German Cancer Research Center, Heidelberg69120, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg69120, Germany
| | - Linda Molla
- Laboratory of Lymphocyte Biology, The Rockefeller University, New York, NY10065
| | - Elias Moris Amro
- Division of Immune Diversity, German Cancer Research Center, Heidelberg69120, Germany
| | - Ignacio L. Ibarra
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg69117, Germany
- Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg85764, Germany
| | - Sandra Ruf
- Division of Immune Diversity, German Cancer Research Center, Heidelberg69120, Germany
| | - Cedrik Neber
- Division of Immune Diversity, German Cancer Research Center, Heidelberg69120, Germany
| | - Christos Gkougkousis
- Division of Immune Diversity, German Cancer Research Center, Heidelberg69120, Germany
| | - Jana Ridani
- Institut de Recherches Cliniques de Montréal, Montréal, QCH2W 1R7, Canada
- Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, QCH4A 3J1, Canada
| | - Poorani Ganesh Subramani
- Institut de Recherches Cliniques de Montréal, Montréal, QCH2W 1R7, Canada
- Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, QCH4A 3J1, Canada
| | - Jonathan Boulais
- Institut de Recherches Cliniques de Montréal, Montréal, QCH2W 1R7, Canada
| | - Dewi Harjanto
- Laboratory of Lymphocyte Biology, The Rockefeller University, New York, NY10065
| | - Alin Vonica
- Department of Biology, Nazareth University, Rochester, NY14618
| | - Javier M. Di Noia
- Institut de Recherches Cliniques de Montréal, Montréal, QCH2W 1R7, Canada
- Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, QCH4A 3J1, Canada
- Department of Medicine, Université de Montréal, Montréal, QCH3C 3J7, Canada
| | - Christoph Dieterich
- Klaus Tschira Institute for Integrative Computational Cardiology, University Hospital Heidelberg, Heidelberg69120, Germany
- German Center for Cardiovascular Research (DZHK) - Partner site Heidelberg/Mannheim, Heidelberg69120, Germany
| | - Judith B. Zaugg
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg69117, Germany
| | - F. Nina Papavasiliou
- Division of Immune Diversity, German Cancer Research Center, Heidelberg69120, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg69120, Germany
- Laboratory of Lymphocyte Biology, The Rockefeller University, New York, NY10065
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11
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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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12
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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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13
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Krylov A, Yu S, Veen K, Newton A, Ye A, Qin H, He J, Jusuf PR. Heterogeneity in quiescent Müller glia in the uninjured zebrafish retina drive differential responses following photoreceptor ablation. Front Mol Neurosci 2023; 16:1087136. [PMID: 37575968 PMCID: PMC10413128 DOI: 10.3389/fnmol.2023.1087136] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 06/23/2023] [Indexed: 08/15/2023] Open
Abstract
Introduction Loss of neurons in the neural retina is a leading cause of vision loss. While humans do not possess the capacity for retinal regeneration, zebrafish can achieve this through activation of resident Müller glia. Remarkably, despite the presence of Müller glia in humans and other mammalian vertebrates, these cells lack an intrinsic ability to contribute to regeneration. Upon activation, zebrafish Müller glia can adopt a stem cell-like state, undergo proliferation and generate new neurons. However, the underlying molecular mechanisms of this activation subsequent retinal regeneration remains unclear. Methods/Results To address this, we performed single-cell RNA sequencing (scRNA-seq) and report remarkable heterogeneity in gene expression within quiescent Müller glia across distinct dorsal, central and ventral retina pools of such cells. Next, we utilized a genetically driven, chemically inducible nitroreductase approach to study Müller glia activation following selective ablation of three distinct photoreceptor subtypes: long wavelength sensitive cones, short wavelength sensitive cones, and rods. There, our data revealed that a region-specific bias in activation of Müller glia exists in the zebrafish retina, and this is independent of the distribution of the ablated cell type across retinal regions. Notably, gene ontology analysis revealed that injury-responsive dorsal and central Müller glia express genes related to dorsal/ventral pattern formation, growth factor activity, and regulation of developmental process. Through scRNA-seq analysis, we identify a shared genetic program underlying initial Müller glia activation and cell cycle entry, followed by differences that drive the fate of regenerating neurons. We observed an initial expression of AP-1 and injury-responsive transcription factors, followed by genes involved in Notch signaling, ribosome biogenesis and gliogenesis, and finally expression of cell cycle, chromatin remodeling and microtubule-associated genes. Discussion Taken together, our findings document the regional specificity of gene expression within quiescent Müller glia and demonstrate unique Müller glia activation and regeneration features following neural ablation. These findings will improve our understanding of the molecular pathways relevant to neural regeneration in the retina.
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Affiliation(s)
- Aaron Krylov
- School of BioSciences, University of Melbourne, Parkville, VIC, Australia
| | - Shuguang Yu
- State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, Chinese Academy of Sciences, Shanghai, China
| | - Kellie Veen
- School of BioSciences, University of Melbourne, Parkville, VIC, Australia
| | - Axel Newton
- School of BioSciences, University of Melbourne, Parkville, VIC, Australia
| | - Aojun Ye
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Huiwen Qin
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Jie He
- State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, Chinese Academy of Sciences, Shanghai, China
| | - Patricia R. Jusuf
- School of BioSciences, University of Melbourne, Parkville, VIC, Australia
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14
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Si TE, Li Z, Zhang J, Su S, Liu Y, Chen S, Peng GH, Cao J, Zang W. Epigenetic mechanisms of Müller glial reprogramming mediating retinal regeneration. Front Cell Dev Biol 2023; 11:1157893. [PMID: 37397254 PMCID: PMC10309042 DOI: 10.3389/fcell.2023.1157893] [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: 02/03/2023] [Accepted: 06/08/2023] [Indexed: 07/04/2023] Open
Abstract
Retinal degenerative diseases, characterized by retinal neuronal death and severe vision loss, affect millions of people worldwide. One of the most promising treatment methods for retinal degenerative diseases is to reprogram non-neuronal cells into stem or progenitor cells, which then have the potential to re-differentiate to replace the dead neurons, thereby promoting retinal regeneration. Müller glia are the major glial cell type and play an important regulatory role in retinal metabolism and retinal cell regeneration. Müller glia can serve as a source of neurogenic progenitor cells in organisms with the ability to regenerate the nervous system. Current evidence points toward the reprogramming process of Müller glia, involving changes in the expression of pluripotent factors and other key signaling molecules that may be regulated by epigenetic mechanisms. This review summarizes recent knowledge of epigenetic modifications involved in the reprogramming process of Müller glia and the subsequent changes to gene expression and the outcomes. In living organisms, epigenetic mechanisms mainly include DNA methylation, histone modification, and microRNA-mediated miRNA degradation, all of which play a crucial role in the reprogramming process of Müller glia. The information presented in this review will improve the understanding of the mechanisms underlying the Müller glial reprogramming process and provide a research basis for the development of Müller glial reprogramming therapy for retinal degenerative diseases.
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Affiliation(s)
- Tian-En Si
- Department of Anatomy, Basic Medical College, Zhengzhou University, Zhengzhou, China
| | - Zhixiao Li
- Department of Anatomy, Basic Medical College, Zhengzhou University, Zhengzhou, China
| | - Jingjing Zhang
- Department of Anatomy, Basic Medical College, Zhengzhou University, Zhengzhou, China
| | - Songxue Su
- Department of Anatomy, Basic Medical College, Zhengzhou University, Zhengzhou, China
| | - Yupeng Liu
- Department of Anatomy, Basic Medical College, Zhengzhou University, Zhengzhou, China
| | - Shiyue Chen
- Department of Anatomy, Basic Medical College, Zhengzhou University, Zhengzhou, China
| | - Guang-Hua Peng
- Department of Pathophysiology, Basic Medical College, Zhengzhou University, Zhengzhou, China
- Laboratory of Visual Cell Differentiation and Regulation, Basic Medical College, Zhengzhou University, Zhengzhou, China
| | - Jing Cao
- Department of Anatomy, Basic Medical College, Zhengzhou University, Zhengzhou, China
| | - Weidong Zang
- Department of Anatomy, Basic Medical College, Zhengzhou University, Zhengzhou, China
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15
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Yin W, Mao X, Xu M, Chen M, Xue M, Su N, Yuan S, Liu Q. Epigenetic regulation in the commitment of progenitor cells during retinal development and regeneration. Differentiation 2023:S0301-4681(23)00023-3. [PMID: 37069005 DOI: 10.1016/j.diff.2023.04.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 04/05/2023] [Accepted: 04/06/2023] [Indexed: 04/19/2023]
Abstract
Retinal development is initiated by multipotent retinal progenitor cells, which undergo several rounds of cell divisions and subsequently terminal differentiation. Retinal regeneration is usually considered as the recapitulation of retinal development, which share common mechanisms underlying the cell cycle re-entry of adult retinal stem cells and the differentiation of retinal neurons. However, how proliferative retinal progenitor cells perform a precise transition to postmitotic retinal cell types during the process of development and regeneration remains elusive. It is proposed that both the intrinsic and extrinsic programming are involved in the transcriptional regulation of the spatio-temporal fate commitment. Epigenetic modifications and the regulatory mechanisms at both DNA and chromatin levels are also postulated to play an important role in the timing of differentiation of specific retinal cells. In the present review, we have summarized recent knowledge of epigenetic regulation that underlies the commitment of retinal progenitor cells in the settings of retinal development and regeneration.
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Affiliation(s)
- Wenjie Yin
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People's Republic of China
| | - Xiying Mao
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People's Republic of China
| | - Miao Xu
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People's Republic of China
| | - Mingkang Chen
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People's Republic of China
| | - Mengting Xue
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People's Republic of China
| | - Na Su
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People's Republic of China
| | - Songtao Yuan
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People's Republic of China.
| | - Qinghuai Liu
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People's Republic of China.
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16
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Mitchell DM, Stenkamp DL. Generating Widespread and Scalable Retinal Lesions in Adult Zebrafish by Intraocular Injection of Ouabain. Methods Mol Biol 2023; 2636:221-235. [PMID: 36881303 PMCID: PMC12068065 DOI: 10.1007/978-1-0716-3012-9_12] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/08/2023]
Abstract
Zebrafish regenerate functional retinal neurons after injury. Regeneration takes place following photic, chemical, mechanical, surgical, or cryogenic lesions, as well as after lesions that selectively target specific neuronal cell populations. An advantage of chemical retinal lesion for studying the process of regeneration is that the lesion is topographically widespread. This results in the loss of visual function as well as a regenerative response that engages nearly all stem cells (Müller glia). Such lesions can therefore be used to further our understanding of the process and mechanisms underlying re-establishment of neuronal wiring patterns, retinal function, and visually mediated behaviors. Widespread chemical lesions also permit the quantitative analysis of gene expression throughout the retina during the period of initial damage and over the duration of regeneration, as well as the study of growth and targeting of axons of regenerated retinal ganglion cells. The neurotoxic Na+/K+ ATPase inhibitor ouabain specifically offers a further advantage over other types of chemical lesions in that it is scalable; the extent of damage can be targeted to include only inner retinal neurons, or all retinal neurons, simply by adjusting the intraocular concentration of ouabain that is used. Here we describe the procedure through which these "selective" vs. "extensive" retinal lesions can be generated.
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Affiliation(s)
- Diana M Mitchell
- Department of Biological Sciences, University of Idaho, Moscow, ID, USA.
| | - Deborah L Stenkamp
- Department of Biological Sciences, University of Idaho, Moscow, ID, USA.
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17
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Barrett LM, Meighan PC, Mitchell DM, Varnum MD, Stenkamp DL. Assessing Rewiring of the Retinal Circuitry by Electroretinogram (ERG) After Inner Retinal Lesion in Adult Zebrafish. Methods Mol Biol 2023; 2636:421-435. [PMID: 36881314 PMCID: PMC12039960 DOI: 10.1007/978-1-0716-3012-9_23] [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: 03/08/2023]
Abstract
Adult zebrafish respond to retinal injury with a regenerative response that replaces damaged neurons with Müller glia-derived regenerated neurons. The regenerated neurons are functional, appear to make appropriate synaptic connections, and support visually mediated reflexes and more complex behaviors. Curiously, the electrophysiology of damaged, regenerating, and regenerated zebrafish retina has only recently been examined. In our previous work, we demonstrated that electroretinogram (ERG) recordings of damaged zebrafish retina correlate with the extent of the inflicted damage and that the regenerated retina at 80 days post-injury exhibited ERG waveforms consistent with functional visual processing. In this paper we describe the procedure for obtaining and analyzing ERG recordings from adult zebrafish previously subjected to widespread lesions that destroy inner retinal neurons and engage a regenerative response that restores retinal function, in particular the synaptic connections between photoreceptor axon terminals and the dendritic trees of retinal bipolar neurons.
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Affiliation(s)
- Lindsey M Barrett
- Department of Biological Sciences, University of Idaho, Moscow, ID, USA
| | - Peter C Meighan
- Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA, USA
| | - Diana M Mitchell
- Department of Biological Sciences, University of Idaho, Moscow, ID, USA
| | - Michael D Varnum
- Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA, USA
| | - Deborah L Stenkamp
- Department of Biological Sciences, University of Idaho, Moscow, ID, USA.
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18
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Vegf signaling between Müller glia and vascular endothelial cells is regulated by immune cells and stimulates retina regeneration. Proc Natl Acad Sci U S A 2022; 119:e2211690119. [PMID: 36469778 PMCID: PMC9897474 DOI: 10.1073/pnas.2211690119] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/08/2022] Open
Abstract
In the zebrafish retina, Müller glia (MG) can regenerate retinal neurons lost to injury or disease. Even though zebrafish MG share structure and function with those of mammals, only in zebrafish do MG function as retinal stem cells. Previous studies suggest dying neurons, microglia/macrophage, and T cells contribute to MG's regenerative response [White et al., Proc. Natl. Acad. Sci. U.S.A. 114, E3719 (2017); Hui et al., Dev. Cell 43, 659 (2017)]. Although MG end-feet abut vascular endothelial (VE) cells to form the blood-retina barrier, a role for VE cells in retina regeneration has not been explored. Here, we report that MG-derived Vegfaa and Pgfa engage Flt1 and Kdrl receptors on VE cells to regulate MG gene expression, Notch signaling, proliferation, and neuronal regeneration. Remarkably, vegfaa and pgfa expression is regulated by microglia/macrophages, while Notch signaling in MG is regulated by a Vegf-dll4 signaling system in VE cells. Thus, our studies link microglia/macrophage, MG, and VE cells in a multicomponent signaling pathway that controls MG reprogramming and proliferation.
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19
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Chucair-Elliott AJ, Ocañas SR, Pham K, Van Der Veldt M, Cheyney A, Stanford D, Gurley J, Elliott MH, Freeman WM. Translatomic response of retinal Müller glia to acute and chronic stress. Neurobiol Dis 2022; 175:105931. [PMID: 36423879 PMCID: PMC9875566 DOI: 10.1016/j.nbd.2022.105931] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 11/14/2022] [Accepted: 11/19/2022] [Indexed: 11/23/2022] Open
Abstract
Analysis of retina cell type-specific epigenetic and transcriptomic signatures is crucial to understanding the pathophysiology of retinal degenerations such as age-related macular degeneration (AMD) and delineating cell autonomous and cell-non-autonomous mechanisms. We have discovered that Aldh1l1 is specifically expressed in the major macroglia of the retina, Müller glia, and, unlike the brain, is not expressed in retinal astrocytes. This allows use of Aldh1l1 cre drivers and Nuclear Tagging and Translating Ribosome Affinity Purification (NuTRAP) constructs for temporally controlled labeling and paired analysis of Müller glia epigenomes and translatomes. As validated through a variety of approaches, the Aldh1l1cre/ERT2-NuTRAP model provides Müller glia specific translatomic and epigenomic profiles without the need to isolate whole cells. Application of this approach to models of acute injury (optic nerve crush) and chronic stress (aging) uncovered few common Müller glia-specific transcriptome changes in inflammatory pathways, and mostly differential signatures for each stimulus. The expression of members of the IL-6 and integrin-linked kinase signaling pathways was enhanced in Müller glia in response to optic nerve crush but not aging. Unique changes in neuroinflammation and fibrosis signaling pathways were observed in response to aging but not with optic nerve crush. The Aldh1l1cre/ERT2-NuTRAP model allows focused molecular analyses of a single, minority cell type within the retina, providing more substantial effect sizes than whole tissue analyses. The NuTRAP model, nucleic acid isolation, and validation approaches presented here can be applied to any retina cell type for which a cell type-specific cre is available.
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Affiliation(s)
- Ana J Chucair-Elliott
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
| | - Sarah R Ocañas
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Kevin Pham
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Michael Van Der Veldt
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Ashley Cheyney
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - David Stanford
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Jami Gurley
- Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Michael H Elliott
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Willard M Freeman
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Oklahoma City Veterans Affairs Medical Center, Oklahoma City, OK, USA.
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20
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Grigoryan EN. Cell Sources for Retinal Regeneration: Implication for Data Translation in Biomedicine of the Eye. Cells 2022; 11:cells11233755. [PMID: 36497013 PMCID: PMC9738527 DOI: 10.3390/cells11233755] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 11/16/2022] [Accepted: 11/22/2022] [Indexed: 11/25/2022] Open
Abstract
The main degenerative diseases of the retina include macular degeneration, proliferative vitreoretinopathy, retinitis pigmentosa, and glaucoma. Novel approaches for treating retinal diseases are based on cell replacement therapy using a variety of exogenous stem cells. An alternative and complementary approach is the potential use of retinal regeneration cell sources (RRCSs) containing retinal pigment epithelium, ciliary body, Müller glia, and retinal ciliary region. RRCSs in lower vertebrates in vivo and in mammals mostly in vitro are able to proliferate and exhibit gene expression and epigenetic characteristics typical for neural/retinal cell progenitors. Here, we review research on the factors controlling the RRCSs' properties, such as the cell microenvironment, growth factors, cytokines, hormones, etc., that determine the regenerative responses and alterations underlying the RRCS-associated pathologies. We also discuss how the current data on molecular features and regulatory mechanisms of RRCSs could be translated in retinal biomedicine with a special focus on (1) attempts to obtain retinal neurons de novo both in vivo and in vitro to replace damaged retinal cells; and (2) investigations of the key molecular networks stimulating regenerative responses and preventing RRCS-related pathologies.
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Affiliation(s)
- Eleonora N Grigoryan
- Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 119334 Moscow, Russia
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21
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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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22
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Catalani E, Cherubini A, Del Quondam S, Cervia D. Regenerative Strategies for Retinal Neurons: Novel Insights in Non-Mammalian Model Organisms. Int J Mol Sci 2022; 23:ijms23158180. [PMID: 35897754 PMCID: PMC9331597 DOI: 10.3390/ijms23158180] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/20/2022] [Accepted: 07/21/2022] [Indexed: 11/16/2022] Open
Abstract
A detailed knowledge of the status of the retina in neurodegenerative conditions is a crucial point for the development of therapeutics in retinal pathologies and to translate eye research to CNS disease. In this context, manipulating signaling pathways that lead to neuronal regeneration offers an excellent opportunity to substitute damaged cells and, thus, restore the tissue functionality. Alternative systems and methods are increasingly being considered to replace/reduce in vivo approaches in the study of retina pathophysiology. Herein, we present recent data obtained from the zebrafish (Danio rerio) and the fruit fly Drosophila melanogaster that bring promising advantages into studying and modeling, at a preclinical level, neurodegeneration and regenerative approaches in retinal diseases. Indeed, the regenerative ability of vertebrate model zebrafish is particularly appealing. In addition, the fruit fly is ideal for regenerative studies due to its high degree of conservation with vertebrates and the broad spectrum of genetic variants achievable. Furthermore, a large part of the drosophila brain is dedicated to sight, thus offering the possibility of studying common mechanisms of the visual system and the brain at once. The knowledge acquired from these alternative models may help to investigate specific well-conserved factors of interest in human neuroregeneration after injuries or during pathologies.
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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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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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25
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DNA methylation maintenance at the p53 locus initiates biliary-mediated liver regeneration. NPJ Regen Med 2022; 7:21. [PMID: 35351894 PMCID: PMC8964678 DOI: 10.1038/s41536-022-00217-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 03/01/2022] [Indexed: 12/13/2022] Open
Abstract
In cases of extensive liver injury, biliary epithelial cells (BECs) dedifferentiate into bipotential progenitor cells (BPPCs), then redifferentiate into hepatocytes and BECs to accomplish liver regeneration. Whether epigenetic regulations, particularly DNA methylation maintenance enzymes, play a role in this biliary-mediated liver regeneration remains unknown. Here we show that in response to extensive hepatocyte damages, expression of dnmt1 is upregulated in BECs to methylate DNA at the p53 locus, which represses p53 transcription, and in turn, derepresses mTORC1 signaling to activate BEC dedifferentiation. After BEC dedifferentiation and BPPC formation, DNA methylation at the p53 locus maintains in BPPCs to continue blocking p53 transcription, which derepresses Bmp signaling to induce BPPC redifferentiation. Thus, this study reveals promotive roles and mechanisms of DNA methylation at the p53 locus in both dedifferentiation and redifferentiation stages of biliary-mediated liver regeneration, implicating DNA methylation and p53 as potential targets to stimulate regeneration after extensive liver injury.
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Wen X, Jiao L, Tan H. MAPK/ERK Pathway as a Central Regulator in Vertebrate Organ Regeneration. Int J Mol Sci 2022; 23:ijms23031464. [PMID: 35163418 PMCID: PMC8835994 DOI: 10.3390/ijms23031464] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/24/2022] [Accepted: 01/25/2022] [Indexed: 02/06/2023] Open
Abstract
Damage to organs by trauma, infection, diseases, congenital defects, aging, and other injuries causes organ malfunction and is life-threatening under serious conditions. Some of the lower order vertebrates such as zebrafish, salamanders, and chicks possess superior organ regenerative capacity over mammals. The extracellular signal-regulated kinases 1 and 2 (ERK1/2), as key members of the mitogen-activated protein kinase (MAPK) family, are serine/threonine protein kinases that are phylogenetically conserved among vertebrate taxa. MAPK/ERK signaling is an irreplaceable player participating in diverse biological activities through phosphorylating a broad variety of substrates in the cytoplasm as well as inside the nucleus. Current evidence supports a central role of the MAPK/ERK pathway during organ regeneration processes. MAPK/ERK signaling is rapidly excited in response to injury stimuli and coordinates essential pro-regenerative cellular events including cell survival, cell fate turnover, migration, proliferation, growth, and transcriptional and translational activities. In this literature review, we recapitulated the multifaceted MAPK/ERK signaling regulations, its dynamic spatio-temporal activities, and the profound roles during multiple organ regeneration, including appendages, heart, liver, eye, and peripheral/central nervous system, illuminating the possibility of MAPK/ERK signaling as a critical mechanism underlying the vastly differential regenerative capacities among vertebrate species, as well as its potential applications in tissue engineering and regenerative medicine.
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27
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Riley SE, Feng Y, Hansen CG. Hippo-Yap/Taz signalling in zebrafish regeneration. NPJ Regen Med 2022; 7:9. [PMID: 35087046 PMCID: PMC8795407 DOI: 10.1038/s41536-022-00209-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 12/14/2021] [Indexed: 12/29/2022] Open
Abstract
The extent of tissue regeneration varies widely between species. Mammals have a limited regenerative capacity whilst lower vertebrates such as the zebrafish (Danio rerio), a freshwater teleost, can robustly regenerate a range of tissues, including the spinal cord, heart, and fin. The molecular and cellular basis of this altered response is one of intense investigation. In this review, we summarise the current understanding of the association between zebrafish regeneration and Hippo pathway function, a phosphorylation cascade that regulates cell proliferation, mechanotransduction, stem cell fate, and tumorigenesis, amongst others. We also compare this function to Hippo pathway activity in the regenerative response of other species. We find that the Hippo pathway effectors Yap/Taz facilitate zebrafish regeneration and that this appears to be latent in mammals, suggesting that therapeutically promoting precise and temporal YAP/TAZ signalling in humans may enhance regeneration and hence reduce morbidity.
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Affiliation(s)
- Susanna E Riley
- University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, Queen's Medical Research Institute, Edinburgh bioQuarter, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK
| | - Yi Feng
- University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, Queen's Medical Research Institute, Edinburgh bioQuarter, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK
| | - Carsten Gram Hansen
- University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, Queen's Medical Research Institute, Edinburgh bioQuarter, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
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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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Gupta S, Adhikary S, Hui SP. Decoding the proregenerative competence of regulatory T cells through complex tissue regeneration in zebrafish. Clin Exp Immunol 2021; 206:346-353. [PMID: 34529822 DOI: 10.1111/cei.13661] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 09/03/2021] [Accepted: 09/07/2021] [Indexed: 12/12/2022] Open
Abstract
Regulatory T cells (Tregs ) are specific subtype of T cells that play a central role in sustaining self-antigen tolerance and restricting inflammatory tissue damage. More recently, additional direct functions of Tregs in mammalian tissue repair have emerged, but the regenerative potential of Tregs in non-mammalian vertebrates has not been explored despite the latter possessing a highly developed adaptive immune system. Why complex organs such as the caudal fin, heart, brain, spinal cord and retina regenerate in certain non-mammalian vertebrates, but not in mammals, is an interesting but unresolved question in the field of regenerative biology. Inflammation has traditionally been thought to be an impediment to regeneration due to the formation of scars. Regenerative decline in higher organisms has been speculated to be the evolutionary advent of adaptive immunity. Recent studies, however, have shown that the innate inflammatory response in non-mammalian organisms is required for organ regeneration. It has also been found that highly advanced adaptive immunity is no longer incompatible with regeneration and for that, Tregs are important. Zebrafish regulatory T cells (zTregs ) migrate rapidly to the injury site in damaged organs, where they facilitate the proliferation of regeneration precursor cells by generating tissue-specific regenerative factors by a process distinct from the canonical anti-inflammatory pathway. We review both reparative and proregenerative roles of Tregs in mammals and zebrafish, respectively, and also give an overview of the forkhead box protein 3 (FoxP3) -dependent immunosuppressive function of Tregs in zebrafish, which makes it a useful model organism for future Treg biology and research.
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Affiliation(s)
- Samudra Gupta
- S. N. Pradhan Centre for Neurosciences, University of Calcutta, Kolkata, India
| | - Satadal Adhikary
- Post Graduate Department of Zoology, ABN Seal College, Cooch Behar, India
| | - Subhra Prakash Hui
- S. N. Pradhan Centre for Neurosciences, University of Calcutta, Kolkata, India
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Grigoryan EN, Markitantova YV. Molecular Strategies for Transdifferentiation of Retinal Pigment Epithelial Cells in Amphibians and Mammals In Vivo. Russ J Dev Biol 2021. [DOI: 10.1134/s1062360421040032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Wu J, Liu LL, Cao M, Hu A, Hu D, Luo Y, Wang H, Zhong JN. DNA methylation plays important roles in retinal development and diseases. Exp Eye Res 2021; 211:108733. [PMID: 34418429 DOI: 10.1016/j.exer.2021.108733] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 08/16/2021] [Accepted: 08/17/2021] [Indexed: 12/16/2022]
Abstract
DNA methylation is important in developing and post-mitotic cells in various tissues. Recent studies have shown that DNA methylation is highly dynamic, and plays important roles during retinal development and aging. In addition, the dynamic regulation of DNA methylation is involved in the occurrence and development of age-related macular degeneration and diabetic retinopathy and shows potential in disease diagnoses and prognoses. This review introduces the epigenetic concepts of DNA methylation and demethylation with an emphasis on their regulatory roles in retinal development and related diseases. Moreover, we propose exciting ideas such as its crosstalk with other epigenetic modifications and retinal regeneration, to provide a potential direction for understanding retinal diseases from the epigenetic perspective.
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Affiliation(s)
- Jing Wu
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of Education, Gannan Medical University, Ganzhou, 341000, Jiangxi Province, China; Department of Ophthalmology, Lishui Municipal Central Hospital, Lishui, 323000, Zhejiang Province, China
| | - Lin-Lin Liu
- Department of Ophthalmology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi Province, China
| | - Miao Cao
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of Education, Gannan Medical University, Ganzhou, 341000, Jiangxi Province, China; Department of Ophthalmology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi Province, China
| | - Ang Hu
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of Education, Gannan Medical University, Ganzhou, 341000, Jiangxi Province, China
| | - Die Hu
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of Education, Gannan Medical University, Ganzhou, 341000, Jiangxi Province, China; Department of Ophthalmology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi Province, China
| | - Yan Luo
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of Education, Gannan Medical University, Ganzhou, 341000, Jiangxi Province, China
| | - Hui Wang
- Department of Ophthalmology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi Province, China.
| | - Jia-Ning Zhong
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of Education, Gannan Medical University, Ganzhou, 341000, Jiangxi Province, China.
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Sahu A, Devi S, Jui J, Goldman D. Notch signaling via Hey1 and Id2b regulates Müller glia's regenerative response to retinal injury. Glia 2021; 69:2882-2898. [PMID: 34415582 DOI: 10.1002/glia.24075] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 08/02/2021] [Accepted: 08/05/2021] [Indexed: 02/01/2023]
Abstract
Zebrafish Müller glia (MG) respond to retinal injury by suppressing Notch signaling and producing progenitors for retinal repair. A certain threshold of injury-derived signal must be exceeded in order to engage MG in a regenerative response (MG's injury-response threshold). Pan-retinal Notch inhibition expands the zone of injury-responsive MG at the site of focal injury, suggesting that Notch signaling regulates MG's injury-response threshold. We found that Notch signaling enhanced chromatin accessibility and gene expression at a subset of regeneration-associated genes in the uninjured retina. Two Notch effector genes, hey1 and id2b, were identified that reflect bifurcation of the Notch signaling pathway, and differentially regulate MG's injury-response threshold and proliferation of MG-derived progenitors. Furthermore, Notch signaling component gene repression in the injured retina suggests a role for Dll4, Dlb, and Notch3 in regulating Notch signaling in MG and epistasis experiments confirm that the Dll4/Dlb-Notch3-Hey1/Id2b signaling pathway regulates MG's injury-response threshold and proliferation.
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Affiliation(s)
- Aresh Sahu
- Michigan Neuroscience Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, USA
| | - Sulochana Devi
- Michigan Neuroscience Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, USA
| | - Jonathan Jui
- Michigan Neuroscience Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, USA
| | - Daniel Goldman
- Michigan Neuroscience Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, USA
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Qian C, Dong B, Wang XY, Zhou FQ. In vivo glial trans-differentiation for neuronal replacement and functional recovery in central nervous system. FEBS J 2021; 288:4773-4785. [PMID: 33351267 PMCID: PMC8217397 DOI: 10.1111/febs.15681] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 12/04/2020] [Accepted: 12/21/2020] [Indexed: 02/07/2023]
Abstract
The adult mammalian central nervous system (CNS) is deficient in intrinsic machineries to replace neurons lost in injuries or progressive degeneration. Various types of these neurons constitute neural circuitries wired to support vital sensory, motor, and cognitive functions. Based on the pioneer studies in cell lineage conversion, one promising strategy is to convert in vivo glial cells into neural progenitors or directly into neurons that can be eventually rewired for functional recovery. We first briefly summarize the well-studied regeneration-capable CNS in the zebrafish, focusing on their postinjury spontaneous reprogramming of the retinal Müller glia (MG). We then compare the signaling transductions, and transcriptional and epigenetic regulations in the zebrafish MGs with their mammalian counterparts, which perpetuate certain barriers against proliferation and neurogenesis and thus fail in MG-to-progenitor conversion. Next, we discuss emerging evidence from mouse studies, in which the in vivo glia-to-neuron conversion could be achieved with sequential or one-step genetic manipulations, such as the conversions from retinal MGs to interneurons, photoreceptors, or retinal ganglion cells (RGCs), as well as the conversions from midbrain astrocytes to dopaminergic or GABAergic neurons. Some of these in vivo studies showed considerable coverage of subtypes in the newly induced neurons and partial reestablishment in neural circuits and functions. Importantly, we would like to point out some crucial technical concerns that need to be addressed to convincingly show successful glia-to-neuron conversion. Finally, we present challenges and future directions in the field for better neural function recovery.
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Affiliation(s)
- Cheng Qian
- Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287
| | - Bryan Dong
- Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287
| | - Xu-Yang Wang
- Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287
| | - Feng-Quan Zhou
- Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287,The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21287,Corresponding author: Feng-Quan Zhou, Ph.D., , Phone: 443-287-5649, Address: The John G. Rangos Building, Room 291, 855 North Wolfe Street, Baltimore, MD 21205, USA
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Insights on the Regeneration Potential of Müller Glia in the Mammalian Retina. Cells 2021; 10:cells10081957. [PMID: 34440726 PMCID: PMC8394255 DOI: 10.3390/cells10081957] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 07/11/2021] [Accepted: 07/26/2021] [Indexed: 12/25/2022] Open
Abstract
Müller glia, the major glial cell types in the retina, maintain retinal homeostasis and provide structural support to retinal photoreceptors. They also possess regenerative potential that might be used for retinal repair in response to injury or disease. In teleost fish (such as zebrafish), the Müller glia response to injury involves reprogramming events that result in a population of proliferative neural progenitors that can regenerate the injured retina. Recent studies have revealed several important mechanisms for the regenerative capacity of Müller glia in fish, which may shed more light on the mechanisms of Müller glia reprogramming and regeneration in mammals. Mammalian Müller glia can adopt stem cell characteristics, and in response to special conditions, be persuaded to proliferate and regenerate, although their native regeneration potential is limited. In this review, we consider the work to date revealing the regenerative potential of the mammalian Müller glia and discuss whether they are a potential source for cell regeneration therapy in humans.
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Koo JW, Wohleb ES. How Stress Shapes Neuroimmune Function: Implications for the Neurobiology of Psychiatric Disorders. Biol Psychiatry 2021; 90:74-84. [PMID: 33485589 PMCID: PMC8126571 DOI: 10.1016/j.biopsych.2020.11.007] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 11/09/2020] [Accepted: 11/11/2020] [Indexed: 12/13/2022]
Abstract
Chronic stress causes physiological and hormonal adaptations that lead to neurobiological consequences and behavioral and cognitive impairments. In particular, chronic stress has been shown to drive reduced neurogenesis and altered synaptic plasticity in brain regions that regulate mood and motivation. The neurobiological and behavioral effects of stress resemble the pathophysiology and symptoms observed in psychiatric disorders, suggesting that there are similar underlying mechanisms. Accumulating evidence indicates that neuroimmune systems, particularly microglia, have a critical role in regulating the neurobiology of stress. Preclinical models indicate that chronic stress provokes changes in microglia phenotype and increases inflammatory cytokine signaling, which affects neuronal function and leads to synaptic plasticity deficits and impaired neurogenesis. More recent work has shown that microglia can also phagocytose neuronal elements and contribute to structural remodeling of neurons in response to chronic stress. In this review we highlight work by the Duman research group (as well as others) that has revealed how chronic stress shapes neuroimmune function and, in turn, how inflammatory mediators and microglia contribute to the neurobiological effects of chronic stress. We also provide considerations to engage the therapeutic potential of neuroimmune systems, with the goal of improving treatment for psychiatric disorders.
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Affiliation(s)
- Ja Wook Koo
- Department of Neural Development and Disease, Korea Brain
Research Institute, Daegu, Korea,Department of Brain and Cognitive Sciences, Daegu Gyeongbuk
Institute of Science and Technology (DGIST), Daegu, Korea
| | - Eric S. Wohleb
- Department of Pharmacology & Systems Physiology,
University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of
America,Corresponding author: Eric S. Wohleb, Department
of Pharmacology & Systems Physiology, University of Cincinnati College of
Medicine, 2120 East Galbraith Road, Cincinnati, OH 45237 U.S.A.,
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George SM, Lu F, Rao M, Leach LL, Gross JM. The retinal pigment epithelium: Development, injury responses, and regenerative potential in mammalian and non-mammalian systems. Prog Retin Eye Res 2021; 85:100969. [PMID: 33901682 DOI: 10.1016/j.preteyeres.2021.100969] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 03/23/2021] [Accepted: 04/07/2021] [Indexed: 12/13/2022]
Abstract
Diseases that result in retinal pigment epithelium (RPE) degeneration, such as age-related macular degeneration (AMD), are among the leading causes of blindness worldwide. Atrophic (dry) AMD is the most prevalent form of AMD and there are currently no effective therapies to prevent RPE cell death or restore RPE cells lost from AMD. An intriguing approach to treat AMD and other RPE degenerative diseases is to develop therapies focused on stimulating endogenous RPE regeneration. For this to become feasible, a deeper understanding of the mechanisms underlying RPE development, injury responses and regenerative potential is needed. In mammals, RPE regeneration is extremely limited; small lesions can be repaired by the expansion of adjacent RPE cells, but large lesions cannot be repaired as remaining RPE cells are unable to functionally replace lost RPE tissue. In some injury paradigms, RPE cells proliferate but do not regenerate a morphologically normal monolayer, while in others, proliferation is pathogenic and results in further disruption to the retina. This is in contrast to non-mammalian vertebrates, which possess tremendous RPE regenerative potential. Here, we discuss what is known about RPE formation during development in mammalian and non-mammalian vertebrates, we detail the processes by which RPE cells respond to injury, and we describe examples of RPE-to-retina and RPE-to-RPE regeneration in non-mammalian vertebrates. Finally, we outline barriers to RPE-dependent regeneration in mammals that could potentially be overcome to stimulate a regenerative response from the RPE.
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Affiliation(s)
- Stephanie M George
- Department of Ophthalmology, Louis J. Fox Center for Vision Restoration, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Fangfang Lu
- Department of Ophthalmology, Louis J. Fox Center for Vision Restoration, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA; Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Mishal Rao
- Department of Ophthalmology, Louis J. Fox Center for Vision Restoration, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Lyndsay L Leach
- Department of Ophthalmology, Louis J. Fox Center for Vision Restoration, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Jeffrey M Gross
- Department of Ophthalmology, Louis J. Fox Center for Vision Restoration, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA; Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
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37
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Campos-Sánchez JC, Esteban MÁ. Review of inflammation in fish and value of the zebrafish model. JOURNAL OF FISH DISEASES 2021; 44:123-139. [PMID: 33236349 DOI: 10.1111/jfd.13310] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 11/09/2020] [Accepted: 11/10/2020] [Indexed: 05/28/2023]
Abstract
Inflammation is a crucial step in the development of chronic diseases in humans. Understanding the inflammation environment and its intrinsic mechanisms when it is produced by harmful stimuli may be a key element in the development of human disease diagnosis. In recent decades, zebrafish (Danio rerio) have been widely used in research, due to their exceptional characteristics, as a model of various human diseases. Interestingly, the mediators released during the inflammatory response of both the immune system and nervous system, after its integration in the hypothalamus, could also facilitate the detection of injury through the register of behavioural changes in the fish. Although there are many studies that give well-defined information separately on such elements as the recruitment of cells, the release of pro- and anti-inflammatory mediators or the type of neurotransmitters released against different triggers, to the best of our knowledge there are no reviews that put all this knowledge together. In the present review, the main available information on inflammation in zebrafish is presented in order to facilitate knowledge about this important process of innate immunity, as well as the stress responses and behavioural changes derived from it.
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Affiliation(s)
- Jose Carlos Campos-Sánchez
- Department of Cell Biology and Histology, Faculty of Biology, Immunobiology for Aquaculture Group, University of Murcia, Murcia, Spain
| | - María Ángeles Esteban
- Department of Cell Biology and Histology, Faculty of Biology, Immunobiology for Aquaculture Group, University of Murcia, Murcia, Spain
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Gao H, A L, Huang X, Chen X, Xu H. Müller Glia-Mediated Retinal Regeneration. Mol Neurobiol 2021; 58:2342-2361. [PMID: 33417229 DOI: 10.1007/s12035-020-02274-w] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 12/22/2020] [Indexed: 12/18/2022]
Abstract
Müller glia originate from neuroepithelium and are the principal glial cells in the retina. During retinal development, Müller glia are one of the last cell types to be born. In lower vertebrates, such as zebrafish, Müller glia possess a remarkable capacity for retinal regeneration following various forms of injury through a reprogramming process in which endogenous Müller glia proliferate and differentiate into all types of retinal cells. In mammals, Müller glia become reactive in response to damage to protect or to further impair retinal function. Although mammalian Müller glia have regenerative potential, it is limited as far as repairing damaged retina. Lessons learned from zebrafish will help reveal the critical mechanisms involved in Müller glia reprogramming. Progress has been made in triggering Müller glia to reprogram and generate functional neurons to restore vision in mammals indicating that Müller glia reprogramming may be a promising therapeutic strategy for human retinal diseases. This review comprehensively summarizes the mechanisms related to retinal regeneration in model animals and the critical advanced progress made in Müller glia reprogramming in mammals.
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Affiliation(s)
- Hui Gao
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China
| | - Luodan A
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China
| | - Xiaona Huang
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China
| | - Xi Chen
- Department of Ophthalmology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Haiwei Xu
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
- Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, China.
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Immunohistochemical Analysis of Histone H3 Modification in Newt Tail Tissue Cells following Amputation. Stem Cells Int 2021; 2021:8828931. [PMID: 33505473 PMCID: PMC7806392 DOI: 10.1155/2021/8828931] [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: 07/14/2020] [Revised: 12/06/2020] [Accepted: 12/15/2020] [Indexed: 11/18/2022] Open
Abstract
Background Newts have impressive regenerative capabilities, but it remains unclear about the role of epigenetic regulation in regeneration process. We herein investigated histone modifications in newt tail tissue cells following amputation. Methods and Results Iberian ribbed male newts (6-8 months old) were suffered to about 1.5 cm length of amputation of their tails for initiating regeneration process, and the residual stump of tail tissues was collected for immunohistochemical analysis 3 days later. Compared to the tissue cells of intact tails, c-kit-positive stem cells and PCNA-positive proliferating cells were significantly higher in tails suffered to amputation (P < 0.001). Amputation also significantly induced the acetylation of H3K9, H3K14, and H3K27 in cells of the tails with amputation (P < 0.001), but did not significantly change the methylation of H3K27 (P = 0.063). Conclusion These results suggest that epigenetic regulation likely involves in newt tail regeneration following amputation.
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Luz-Madrigal A, Grajales-Esquivel E, Tangeman J, Kosse S, Liu L, Wang K, Fausey A, Liang C, Tsonis PA, Del Rio-Tsonis K. DNA demethylation is a driver for chick retina regeneration. Epigenetics 2020; 15:998-1019. [PMID: 32290791 PMCID: PMC7518676 DOI: 10.1080/15592294.2020.1747742] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 02/26/2020] [Accepted: 03/09/2020] [Indexed: 01/01/2023] Open
Abstract
Cellular reprogramming resets the epigenetic landscape to drive shifts in transcriptional programmes and cell identity. The embryonic chick can regenerate a complete neural retina, after retinectomy, via retinal pigment epithelium (RPE) reprogramming in the presence of FGF2. In this study, we systematically analysed the reprogramming competent chick RPE prior to injury, and during different stages of reprogramming. In addition to changes in the expression of genes associated with epigenetic modifications during RPE reprogramming, we observed dynamic changes in histone marks associated with bivalent chromatin (H3K27me3/H3K4me3) and intermediates of the process of DNA demethylation including 5hmC and 5caC. Comprehensive analysis of the methylome by whole-genome bisulphite sequencing (WGBS) confirmed extensive rearrangements of DNA methylation patterns including differentially methylated regions (DMRs) found at promoters of genes associated with chromatin organization and fibroblast growth factor production. We also identified Tet methylcytosine dioxygenase 3 (TET3) as an important factor for DNA demethylation and retina regeneration, capable of reprogramming RPE in the absence of exogenous FGF2. In conclusion, we demonstrate that injury early in RPE reprogramming triggers genome-wide dynamic changes in chromatin, including bivalent chromatin and DNA methylation. In the presence of FGF2, these dynamic modifications are further sustained in the commitment to form a new retina. Our findings reveal active DNA demethylation as an important process that may be applied to remove the epigenetic barriers in order to regenerate retina in mammals. ABBREVIATIONS bp: Base pair; DMR: Differentially methylated region; DMC: Differentially methylated cytosines; GFP: Green fluorescent protein; PCR: Polymerase chain reaction. TET: Ten-eleven translocation; RPE: retinal pigment epithelium.
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Affiliation(s)
- Agustín Luz-Madrigal
- Department of Biology and Center for Visual Sciences at Miami University, Miami University, Oxford, OH, USA
- Department of Biology and Center for Stem Cell & Organoid Medicine (CuSTOM), Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - Erika Grajales-Esquivel
- Department of Biology and Center for Visual Sciences at Miami University, Miami University, Oxford, OH, USA
| | - Jared Tangeman
- Department of Biology and Center for Visual Sciences at Miami University, Miami University, Oxford, OH, USA
| | - Sarah Kosse
- Department of Biology and Center for Visual Sciences at Miami University, Miami University, Oxford, OH, USA
| | - Lin Liu
- Department of Biology and Center for Visual Sciences at Miami University, Miami University, Oxford, OH, USA
| | - Kai Wang
- Department of Biology and Center for Visual Sciences at Miami University, Miami University, Oxford, OH, USA
| | - Andrew Fausey
- Department of Biology and Center for Visual Sciences at Miami University, Miami University, Oxford, OH, USA
| | - Chun Liang
- Department of Biology and Center for Visual Sciences at Miami University, Miami University, Oxford, OH, USA
- Department of Computer Science and Software Engineering, Miami University, Oxford, OH, USA
| | - Panagiotis A. Tsonis
- Department of Biology, University of Dayton and Center for Tissue Regeneration and Engineering at the University of Dayton (TREND), Dayton, OH, USA
| | - Katia Del Rio-Tsonis
- Department of Biology and Center for Visual Sciences at Miami University, Miami University, Oxford, OH, USA
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Kara N, Kent MR, Didiano D, Rajaram K, Zhao A, Summerbell ER, Patton JG. The miR-216a-Dot1l Regulatory Axis Is Necessary and Sufficient for Müller Glia Reprogramming during Retina Regeneration. Cell Rep 2020; 28:2037-2047.e4. [PMID: 31433981 PMCID: PMC6750267 DOI: 10.1016/j.celrep.2019.07.061] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 06/13/2019] [Accepted: 07/18/2019] [Indexed: 12/15/2022] Open
Abstract
Unlike the adult mammalian retina, Müller glia (MG) in the adult zebrafish retina are able to dedifferentiate into a ‘‘stem cell’’-like state and give rise to multipotent progenitor cells upon retinal damage. We show that miR-216a is downregulated in MG after constant intense light lesioning and that miR-216a suppression is necessary and sufficient for MG dedifferentiation and proliferation during retina regeneration. miR-216a targets the H3K79 methyltransferase Dot1l, which is upregulated in proliferating MG after retinal damage. Loss-of-function experiments show that Dot1l is necessary for MG reprogramming and mediates MG proliferation downstream of miR-216a. We further demonstrate that miR-216a and Dot1l regulate MG-mediated retina regeneration through canonical Wnt signaling. This article reports a regulatory mechanism upstream of Wnt signaling during retina regeneration and provides potential targets for enhancing regeneration in the adult mammalian retina. Unlike the adult mammalian retina, Müller glia in the adult zebrafish retina are able to reprogram into a stem cell-like state and give rise to multipotent progenitor cells upon retinal damage. Kara et al. show that miR-216a suppression stimulates Müller glia reprogramming through upregulation of the H3K79 methyltransferase Dot1l and activation of Wnt/β-catenin signaling.
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Affiliation(s)
- Nergis Kara
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
| | - Matthew R Kent
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
| | - Dominic Didiano
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
| | - Kamya Rajaram
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
| | - Anna Zhao
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
| | - Emily R Summerbell
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
| | - James G Patton
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA.
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42
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Grigoryan EN. Potential Endogenous Cell Sources for Retinal Regeneration in Vertebrates and Humans: Progenitor Traits and Specialization. Biomedicines 2020; 8:E208. [PMID: 32664635 PMCID: PMC7400588 DOI: 10.3390/biomedicines8070208] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 07/04/2020] [Accepted: 07/10/2020] [Indexed: 12/11/2022] Open
Abstract
Retinal diseases often cause the loss of photoreceptor cells and, consequently, impairment of vision. To date, several cell populations are known as potential endogenous retinal regeneration cell sources (RRCSs): the eye ciliary zone, the retinal pigment epithelium, the iris, and Müller glia. Factors that can activate the regenerative responses of RRCSs are currently under investigation. The present review considers accumulated data on the relationship between the progenitor properties of RRCSs and the features determining their differentiation. Specialized RRCSs (all except the ciliary zone in low vertebrates), despite their differences, appear to be partially "prepared" to exhibit their plasticity and be reprogrammed into retinal neurons due to the specific gene expression and epigenetic landscape. The "developmental" characteristics of RRCS gene expression are predefined by the pathway by which these cell populations form during eye morphogenesis; the epigenetic features responsible for chromatin organization in RRCSs are under intracellular regulation. Such genetic and epigenetic readiness is manifested in vivo in lower vertebrates and in vitro in higher ones under conditions permissive for cell phenotype transformation. Current studies on gene expression in RRCSs and changes in their epigenetic landscape help find experimental approaches to replacing dead cells through recruiting cells from endogenous resources in vertebrates and humans.
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Affiliation(s)
- Eleonora N Grigoryan
- Koltsov Institute of Developmental Biology, Russian Academy of Sciences, 119334 Moscow, Russia
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43
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García-García D, Locker M, Perron M. Update on Müller glia regenerative potential for retinal repair. Curr Opin Genet Dev 2020; 64:52-59. [PMID: 32619816 DOI: 10.1016/j.gde.2020.05.025] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 05/08/2020] [Accepted: 05/24/2020] [Indexed: 12/20/2022]
Abstract
Retinal regeneration efficiency from Müller glia varies tremendously among vertebrate species, being extremely limited in mammals. Efforts towards the identification of molecular mechanisms underlying Müller cell proliferative and neurogenic potential should help finding strategies to awake them and ensure regeneration in mammals. We provide here an update on the most recent and original progresses made in the field. These include remarkable discoveries regarding (i) unprecedented cross-species comparison of Müller cell transcriptome using single-cell technologies, (ii) the identification of new strategies to promote both the proliferative and the neurogenic potential of mammalian Müller cells, (iii) the role of the epigenome in regulating Müller glia plasticity, (iv) miRNA-based regulatory mechanisms of Müller cell response to injury, and (v) the influence of inflammatory signals on the regenerative process.
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Affiliation(s)
- Diana García-García
- Université Paris-Saclay, CNRS, Retina France, Institut des Neurosciences Paris Saclay, Orsay, France
| | - Morgane Locker
- Université Paris-Saclay, CNRS, Retina France, Institut des Neurosciences Paris Saclay, Orsay, France
| | - Muriel Perron
- Université Paris-Saclay, CNRS, Retina France, Institut des Neurosciences Paris Saclay, Orsay, France.
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44
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Schumacker ST, Coppage KR, Enke RA. RNA sequencing analysis of the human retina and associated ocular tissues. Sci Data 2020; 7:199. [PMID: 32581312 PMCID: PMC7314755 DOI: 10.1038/s41597-020-0541-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 06/02/2020] [Indexed: 11/08/2022] Open
Abstract
The retina is a stratified layer of sensory neurons lining the posterior portion of the eye. In humans, fine detail and color vision are enabled by the macula, a central region of the retina dense in cone photoreceptors (PRs). Achromatic low light and peripheral vision are facilitated by rod PRs found with increasing density outside the macula in the peripheral retina. The outer retina is nourished by choroidal blood flow regulated by a single layer of intervening retinal pigment epithelial (RPE) cells. Existing human retinal transcriptome projects have been critical for studying aspects of retinal development and disease however, there are currently no publicly available data sets accurately describing the aging human central retina, peripheral retina, and supporting RPE/choroid. Here we used Illumina RNA sequencing (RNA-seq) analysis to characterize the mRNA transcriptome of rod and cone PR-enriched human retina as well as supporting macular RPE/choroid tissue. These data will be valuable to the vision research community for characterizing global changes in gene expression in clinically relevant ocular tissues.
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Affiliation(s)
- Scott T Schumacker
- Department of Biology, James Madison University, Harrisonburg, VA, 22807, USA
| | - Krista R Coppage
- Department of Biology, James Madison University, Harrisonburg, VA, 22807, USA
| | - Ray A Enke
- Department of Biology, James Madison University, Harrisonburg, VA, 22807, USA.
- Center for Genome & Metagenome Studies, James Madison University, Harrisonburg, VA, 22807, USA.
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45
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Lee MS, Wan J, Goldman D. Tgfb3 collaborates with PP2A and notch signaling pathways to inhibit retina regeneration. eLife 2020; 9:e55137. [PMID: 32396062 PMCID: PMC7250569 DOI: 10.7554/elife.55137] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 05/12/2020] [Indexed: 12/14/2022] Open
Abstract
Neuronal degeneration in the zebrafish retina stimulates Müller glia (MG) to proliferate and generate multipotent progenitors for retinal repair. Controlling this proliferation is critical to successful regeneration. Previous studies reported that retinal injury stimulates pSmad3 signaling in injury-responsive MG. Contrary to these findings, we report pSmad3 expression is restricted to quiescent MG and suppressed in injury-responsive MG. Our data indicates that Tgfb3 is the ligand responsible for regulating pSmad3 expression. Remarkably, although overexpression of either Tgfb1b or Tgfb3 can stimulate pSmad3 expression in the injured retina, only Tgfb3 inhibits injury-dependent MG proliferation; suggesting the involvement of a non-canonical Tgfb signaling pathway. Furthermore, inhibition of Alk5, PP2A or Notch signaling rescues MG proliferation in Tgfb3 overexpressing zebrafish. Finally, we report that this Tgfb3 signaling pathway is active in zebrafish MG, but not those in mice, which may contribute to the different regenerative capabilities of MG from fish and mammals.
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Affiliation(s)
- Mi-Sun Lee
- Michigan Neuroscience Institute and Department of Biological Chemistry, University of MichiganAnn ArborUnited States
| | - Jin Wan
- Michigan Neuroscience Institute and Department of Biological Chemistry, University of MichiganAnn ArborUnited States
| | - Daniel Goldman
- Michigan Neuroscience Institute and Department of Biological Chemistry, University of MichiganAnn ArborUnited States
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46
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Abstract
In humans, various genetic defects or age-related diseases, such as diabetic retinopathies, glaucoma, and macular degeneration, cause the death of retinal neurons and profound vision loss. One approach to treating these diseases is to utilize stem and progenitor cells to replace neurons in situ, with the expectation that new neurons will create new synaptic circuits or integrate into existing ones. Reprogramming non-neuronal cells in vivo into stem or progenitor cells is one strategy for replacing lost neurons. Zebrafish have become a valuable model for investigating cellular reprogramming and retinal regeneration. This review summarizes our current knowledge regarding spontaneous reprogramming of Müller glia in zebrafish and compares this knowledge to research efforts directed toward reprogramming Müller glia in mammals. Intensive research using these animal models has revealed shared molecular mechanisms that make Müller glia attractive targets for cellular reprogramming and highlighted the potential for curing degenerative retinal diseases from intrinsic cellular sources.
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Affiliation(s)
- Manuela Lahne
- Center for Zebrafish Research, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, USA; , .,Center for Stem Cells and Regenerative Medicine, University of Notre Dame, Notre Dame, Indiana 46556, USA
| | - Mikiko Nagashima
- Department of Ophthalmology and Visual Sciences, University of Michigan School of Medicine, Ann Arbor, Michigan 48105, USA; ,
| | - David R Hyde
- Center for Zebrafish Research, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, USA; , .,Center for Stem Cells and Regenerative Medicine, University of Notre Dame, Notre Dame, Indiana 46556, USA
| | - Peter F Hitchcock
- Department of Ophthalmology and Visual Sciences, University of Michigan School of Medicine, Ann Arbor, Michigan 48105, USA; , .,Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, Michigan 48105, USA
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47
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Markitantova YV, Simirskii VN. Role of the Redox System in Initiation of a Regenerative Response of Neural Eye Tissues in Vertebrates. Russ J Dev Biol 2020. [DOI: 10.1134/s106236042001004x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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48
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Tingle CF, Magnuson B, Zhao Y, Heisel CJ, Kish PE, Kahana A. Paradoxical Changes Underscore Epigenetic Reprogramming During Adult Zebrafish Extraocular Muscle Regeneration. Invest Ophthalmol Vis Sci 2020; 60:4991-4999. [PMID: 31794598 PMCID: PMC6890397 DOI: 10.1167/iovs.19-27556] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Purpose Genomic reprogramming and cellular dedifferentiation are critical to the success of de novo tissue regeneration in lower vertebrates such as zebrafish and axolotl. In tissue regeneration following injury or disease, differentiated cells must retain lineage while assuming a progenitor-like identity in order to repopulate the damaged tissue. Understanding the epigenetic regulation of programmed cellular dedifferentiation provides unique insights into the biology of stem cells and cancer and may lead to novel approaches for treating human degenerative conditions. Methods Using a zebrafish in vivo model of adult muscle regeneration, we utilized chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq) to characterize early changes in epigenetic signals, focusing on three well-studied histone modifications-histone H3 trimethylated at lysine 4 (H3K4me3), and histone H3 trimethylated or acetylated at lysine 27 (H3K27me3 and H3K27Ac, respectively). Results We discovered that zebrafish myocytes undergo a global, rapid, and transient program to drive genomic remodeling. The timing of these epigenetic changes suggests that genomic reprogramming itself represents a distinct sequence of events, with predetermined checkpoints, to generate cells capable of de novo regeneration. Importantly, we uncovered subsets of genes that maintain epigenetic marks paradoxical to changes in expression, underscoring the complexity of epigenetic reprogramming. Conclusions Within our model, histone modifications previously associated with gene expression act for the most part as expected, with exceptions suggesting that zebrafish chromatin maintains an easily editable state with a number of genes paradoxically marked for transcriptional activity despite downregulation.
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Affiliation(s)
- Christina F Tingle
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, United States
| | - Brian Magnuson
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, United States.,Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan, United States
| | - Yi Zhao
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, United States
| | - Curtis J Heisel
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, United States.,University of Michigan Medical School, Ann Arbor, Michigan, United States
| | - Phillip E Kish
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, United States
| | - Alon Kahana
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, United States.,Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, United States
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49
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Markitantova Y, Simirskii V. Inherited Eye Diseases with Retinal Manifestations through the Eyes of Homeobox Genes. Int J Mol Sci 2020; 21:E1602. [PMID: 32111086 PMCID: PMC7084737 DOI: 10.3390/ijms21051602] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 02/21/2020] [Accepted: 02/24/2020] [Indexed: 12/14/2022] Open
Abstract
Retinal development is under the coordinated control of overlapping networks of signaling pathways and transcription factors. The paper was conceived as a review of the data and ideas that have been formed to date on homeobox genes mutations that lead to the disruption of eye organogenesis and result in inherited eye/retinal diseases. Many of these diseases are part of the same clinical spectrum and have high genetic heterogeneity with already identified associated genes. We summarize the known key regulators of eye development, with a focus on the homeobox genes associated with monogenic eye diseases showing retinal manifestations. Recent advances in the field of genetics and high-throughput next-generation sequencing technologies, including single-cell transcriptome analysis have allowed for deepening of knowledge of the genetic basis of inherited retinal diseases (IRDs), as well as improve their diagnostics. We highlight some promising avenues of research involving molecular-genetic and cell-technology approaches that can be effective for IRDs therapy. The most promising neuroprotective strategies are aimed at mobilizing the endogenous cellular reserve of the retina.
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50
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Seritrakul P, Gross JM. Genetic and epigenetic control of retinal development in zebrafish. Curr Opin Neurobiol 2019; 59:120-127. [PMID: 31255843 PMCID: PMC6888853 DOI: 10.1016/j.conb.2019.05.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 04/23/2019] [Accepted: 05/28/2019] [Indexed: 12/24/2022]
Abstract
The vertebrate retina is a complex structure composed of seven cell types (six neuron and one glia), and all of which originate from a seemingly homogeneous population of proliferative multipotent retinal progenitor cells (RPCs) that exit the cell cycle and differentiate in a spatio-temporally regulated and stereotyped fashion. This neurogenesis process requires intricate genetic regulation involving a combination of cell intrinsic transcription factors and extrinsic signaling molecules, and many critical factors have been identified that influence the timing and composition of the developing retina. Adding complexity to the process, over the past decade, a variety of epigenetic regulatory mechanisms have been shown to influence neurogenesis, and these include changes in histone modifications and the chromatin landscape and changes in DNA methylation and hydroxymethylation patterns. This review summarizes recent findings in the genetic and epigenetic regulation of retinal development, with an emphasis on the zebrafish model system, and it outlines future areas of investigation that will continue to push the field forward into the epigenomics era.
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Affiliation(s)
- Pawat Seritrakul
- Faculty of Animal Sciences and Agricultural Technology, Silpakorn University, Phetchaburi, 76120, Thailand.
| | - Jeffrey M Gross
- Departments of Ophthalmology, and Developmental Biology, The Louis J. Fox Center for Vision Restoration, The McGowan Institute for Regenerative Medicine, The University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States.
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