Evidence of Müller Glia Conversion Into Retina Ganglion Cells Using Neurogenin2

Guimarães, Roberta Pereira de Melo; Landeira, Bruna Soares; Coelho, Diego Marques; Golbert, Daiane Cristina Ferreira; Silveira, Mariana S.; Linden, Rafael; Reis, Ricardo Augusto de Melo; Costa, Marcos Romualdo

doi:10.3389/fncel.2018.00410

Cited by 33 publications

(24 citation statements)

References 66 publications

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“…The Müller glia has been gathering attention due to its proliferative properties after retinal injury and activation of stem/progenitor cell phenotype, allowing a return to the cell cycle and eventually differentiating into functional neurons. This has been shown for neurogenin 2 or ASCL1, transcriptional factors that, when nucleofected onto Müller glia, were reprogrammed into inducible neurons ( Guimaraes et al, 2018 ), functionally monitored in terms of calcium imaging. This strategy has been used by many groups to partially restore vision in different animal models ( Hampton, 2018 ).…”

Section: Retina a Central Modelmentioning

confidence: 92%

Cell Calcium Imaging as a Reliable Method to Study Neuron–Glial Circuits

2020

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Complex dynamic cellular networks have been studied in physiological and pathological processes under the light of single-cell calcium imaging (SCCI), a method that correlates functional data based on calcium shifts operated by different intracellular and extracellular mechanisms integrated with their cell phenotypes. From the classic synaptic structure to tripartite astrocytic model or the recent quadripartite microglia added ensemble, as well as other physiological tissues, it is possible to follow how cells signal spatiotemporally to cellular patterns. This methodology has been used broadly due to the universal properties of calcium as a second messenger. In general, at least two types of receptor operate through calcium permeation: a fast-acting ionotropic receptor channel and a slow-activating metabotropic receptor, added to exchangers/transporters/pumps and intracellular Ca 2+ release activated by messengers. These prototypes have gained an enormous amount of information in dynamic signaling circuits. SCCI has also been used as a method to associate phenotypic markers during development and stage transitions in progenitors, stem, vascular cells, neuro- and glioblasts, neurons, astrocytes, oligodendrocytes, and microglia that operate through ion channels, transporters, and receptors. Also, cancer cells or inducible cell lines from human organoids characterized by transition stages are currently being used to model diseases or reconfigure healthy cells in terms of the expression of calcium-binding/permeable molecules and shed light on therapy.

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Section: Retina a Central Modelmentioning

confidence: 92%

Cell Calcium Imaging as a Reliable Method to Study Neuron–Glial Circuits

2020

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“…Ectopic expression of NGN2 contributed to the production of a pool of neurons with expression of photoreceptor genes, amacrine cells, and ganglion layer cells. The authors also showed that the presence of mitogenic factors, such as EGF or bFGF, which stimulate the proliferation of mouse Müller glia cells increased the effectiveness of direct reprogramming (Guimarães et al, 2018). Proliferation is one of the passive ways to remove the methylation of DNA, epigenetic memory, which increases the effectiveness of direct reprogramming (Masserdotti et al, 2016;Kim and Costello, 2017).…”

Section: The Role Of Factors Of Cellular Specialization and Differentmentioning

confidence: 99%

“…Another highly plastic type of retinal cell, Müller glia cells, also has an intrinsic ability to be directly reprogrammed. Guimarães et al (2018) have shown that retinal ganglion cells in mice can be obtained from postnatal Müller glia cells by overexpression of NGN2. Ectopic expression of NGN2 contributed to the production of a pool of neurons with expression of photoreceptor genes, amacrine cells, and ganglion layer cells.…”

Section: The Role Of Factors Of Cellular Specialization and Differentmentioning

confidence: 99%

“…Degeneration of the retinal ganglion layer cells is the main sign of glaucoma that affects the elderly; the restoration of ganglion cells is among the most important tasks, as is the restoration of photoreceptors (Guimarães et al, 2018). Ma et al (2009a) showed the participation of the SOX2 transcription factor, belonging to the Sox family, in the induction of expression of markers of the ganglion and amacrine neurons in chicken embryonic RPE cells in vivo and in vitro and in inhibiting the expression of RPE-specific genes.…”

Section: The Role Of Factors Of Cellular Specialization and Differentmentioning

confidence: 99%

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Reprogramming of Differentiated Mammalian and Human Retinal Pigment Epithelium: Current Achievements and Prospects

2020

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Impairment of the homeostatic and functional integrity of the retina and retinal pigment epithelium (RPE) is the main cause of some degenerative diseases of the human eye, which are accompanied by loss of eyesight. Despite the significant progress made over the past decades in the development of new methods for treatment for this pathology, there are still several complications when using surgical methods for correction of eyesight and so far insurmountable limitations in the applications of modern approaches, such as gene therapy and genetic engineering. One of the promising approaches to the treatment of degenerative diseases of the retina may be an approach based on the application of regenerative capacities of its endogenous cells with high plasticity, in particular, of RPE cells and Müller glia. Currently, vertebrate RPE cells are of great interest as a source of new photoreceptors and other neurons in the degrading retina in vivo. In this regard, the possibilities of their direct reprogramming by genetic, epigenetic, and chemical methods and their combination are being investigated. This review focuses on research in gene-directed reprogramming of vertebrate RPE cells into retinal neurons, with detailed analysis of the genes used as the main reprogramming factors, comparative analysis, and extrapolation of experimental data from animals to humans. Also, this review covers studies on the application of alternative approaches to gene-directed reprogramming, such as chemicalmediated reprogramming with the use of cocktails of therapeutic low-molecular-weight compounds and microRNAs. In general, the research results indicate the complexity of the process for direct reprogramming of human RPE cells into retinal neurons. However, taking into account the results of direct reprogramming of vertebrate cells and the accessibility of human RPE cells for various vectors that deliver a variety of molecules to cells, such as transcription factors, chimeric endonucleases, recombinant proteins, and low-weight molecular compounds, the most optimal combination of factors for the successful conversion of human RPE cells to retinal neurons can be suggested.

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“…The search for ways to unlock this regenerative potential in mammals has increasingly attracted interest (Karl et al, 2008;Loffler et al, 2015;Ueki et al, 2015;Jorstad et al, 2017;Guimaraes et al, 2018;Yao et al, 2018). Pollak et al (2013) demonstrated that the overexpression of Ascl1 in Müller glia cultures and mouse retinal explants change gene expression with downregulation of glial genes and upregulation of progenitor genes.…”

Section: Regeneration From Endogenous Sources: Müller Gliamentioning

confidence: 99%

On the Generation and Regeneration of Retinal Ganglion Cells

Oliveira-Valença

Bosco

Vetter

et al. 2020

Front. Cell Dev. Biol.

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Retinal development follows a conserved neurogenic program in vertebrates to orchestrate the generation of specific cell types from multipotent progenitors in sequential but overlapping waves. In this program, retinal ganglion cells (RGCs) are the first cell type generated. RGCs are the final output neurons of the retina and are essential for vision and circadian rhythm. Key molecular steps have been defined in multiple vertebrate species to regulate competence, specification, and terminal differentiation of this cell type. This involves neuronal-specific transcription factor networks, regulators of chromatin dynamics and miRNAs. In mammals, RGCs and their optic nerve axons undergo neurodegeneration and loss in glaucoma and other optic neuropathies, resulting in irreversible vision loss. The incapacity of RGCs and axons to regenerate reinforces the need for the design of efficient RGC replacement strategies. Here we describe the essential molecular pathways for the differentiation of RGCs in vertebrates, as well as experimental manipulations that extend the competence window for generation of this early cell type from late progenitors. We discuss recent advances in regeneration of retinal neurons in vivo in both mouse and zebrafish and discuss possible strategies and barriers to achieving RGC regeneration as a therapeutic approach for vision restoration in blinding diseases such as glaucoma.

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Evidence of Müller Glia Conversion Into Retina Ganglion Cells Using Neurogenin2

Cited by 33 publications

References 66 publications

Cell Calcium Imaging as a Reliable Method to Study Neuron–Glial Circuits

Cell Calcium Imaging as a Reliable Method to Study Neuron–Glial Circuits

Reprogramming of Differentiated Mammalian and Human Retinal Pigment Epithelium: Current Achievements and Prospects

On the Generation and Regeneration of Retinal Ganglion Cells

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