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Reprogramming Muller glia to regenerate ganglion-like cells in adult mouse retina with developmental transcription factors.

ABSTRACT: Many neurodegenerative diseases cause degeneration of specific types of neurons. For example, glaucoma leads to death of retinal ganglion cells, leaving other neurons intact. Neurons are not regenerated in the adult mammalian central nervous system. However, in non-mammalian vertebrates, glial cells spontaneously reprogram into neural progenitors and replace neurons after injury. We have recently developed strategies to stimulate regeneration of functional neurons in the adult mouse retina by overexpressing the proneural factor Ascl1 in Müller glia. In this report, we test additional transcription factors (TFs) for their ability to direct regeneration to particular types of retinal neurons. We engineered mice to express different combinations of TFs in MG, including Ascl1, Pou4f2, Islet1 and Atoh1. Using IHC, scRNA-seq, scATAC-seq, and electrophysiology we find retinal ganglion-like cells can be regenerated in the damaged adult mouse retina in vivo with targeted overexpression of developmental RGC-transcription factors.

ORGANISM(S): Mus musculus

PROVIDER: GSE211077 | GEO | 2022/09/15

REPOSITORIES: GEO

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Stimulation of functional neuronal regeneration from Müller glia in adult mice

Project description:Many retinal diseases lead to the loss of retinal neurons and cause visual impairment. The adult mammalian retina has little capacity for regeneration. By contrast, teleost fish functionally regenerate their retina following injury, and Müller glia (MG) are the source of regenerated neurons. The proneural transcription factor Ascl1 is upregulated in MG after retinal damage in zebrafish and is necessary for regeneration. Although Ascl1 is not expressed in mammalian MG after injury, forced expression of Ascl1 in mouse MG induces a neurogenic state in vitro and in vivo after NMDA (N-methyl-d-aspartate) damage in young mice. However, by postnatal day 16, mouse MG lose neurogenic capacity, despite Ascl1 overexpression. Loss of neurogenic capacity in mature MG is accompanied by reduced chromatin accessibility, suggesting that epigenetic factors limit regeneration. Here we show that MG-specific overexpression of Ascl1, together with a histone deacetylase inhibitor, enables adult mice to generate neurons from MG after retinal injury. The MG-derived neurons express markers of inner retinal neurons, synapse with host retinal neurons, and respond to light. Using an assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), we show that the histone deacetylase inhibitor promotes accessibility at key gene loci in the MG, and allows more effective reprogramming. Our results thus provide a new approach for the treatment of blinding retinal diseases.

2021-01-10 | GSE164489 | GEO

Efficient stimulation of retinal regeneration from Muller glia in adult mice using combinations of proneural bHLH transcription factors.

Project description:Regenerative neuroscience aims to stimulate endogenous repair mechanisms in the nervous system to replace neurons that have been lost from degenerative diseases or trauma. In the retina, many non-mammalian vertebrate species spontaneously regenerate retinal neurons from glial cells, through an injury-induced reprogramming of the cells to a retinal progenitor state. Recently, we have reported that engineering mouse Muller glia to express a retinal progenitor gene, the proneural transcription factor, Ascl1, is sufficient to stimulate neurogenesis in the glia to generate functional neurons. However, this process is inefficient and only a third of the Ascl1-expressing glia generate new neurons. Here we test whether proneural transcription factors of the Atoh1/7 class can further promote the neurogenic capacity of MG. We report that the combination of Ascl1:Atoh1 is remarkably efficient at stimulating neurogenesis (>80% expressing cells), even in the absence of retinal injury or TSA. We use electrophysiology and scRNA-seq to demonstrate that Ascl1:Atoh1 generates a diversity of retinal neuron types with the majority expressing characteristics of retinal ganglion cells. Overall, our results provide a proof-of-principle that transcription factors that are normally sequentially active in cell fate specification, can when combined, substantially improve glial reprogramming to neurons and expand the repertoire of cell fates that can be regenerated in the adult mouse retina. The ability to stimulate the neurogenic potential of glia in adult mice with high efficiency is a key step towards translation of this approach to repair the central nervous system.

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Direct induction of retinal ganglion cell-like neurons

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The impact of timing and injury mode on induced neurogenesis in the adult mammalian retina

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Transcription profiling of zebrafish retinal development and photoreceptor regeneration to investigate the roles of midkine-a and midkine-b

Project description:In the retina of adult teleosts, stem cells are sustained in two specialized niches: the ciliary marginal zone (CMZ) and the microenvironment surrounding adult MÃ¼ller glia. Recently, MÃ¼ller glia were identified as the regenerative stem cells in the teleost retina. Secreted signaling molecules that regulate neuronal regeneration in the retina are largely unknown. In a microarray screen to discover such factors, we identified midkine-b (mdkb). Midkine is a highly conserved heparin-binding growth factor with numerous biological functions. The zebrafish genome encodes two distinct midkine genes: mdka and mdkb. Here, we describe the cellular expression of mdka and mdkb during retinal development and the initial, proliferative phase of photoreceptor regeneration. The results show that in the embryonic and larval retina mdka and mdkb are expressed in stem cells, retinal progenitors and neurons in distinct patterns that suggest different functions for the two molecules. Following the selective death of photoreceptors in the adult, mdka and mdkb are co-expressed in horizontal cells and proliferating MÃ¼ller glia and their neurogenic progeny. These data reveal that Mdka and Mdkb are signaling factors present in the retinal stem cell niches in both embryonic and mature retinas, and that their cellular expression is actively modulated during retinal development and regeneration. Experiment Overall Design: As a means to identify genes necessary for photoreceptor regeneration, we evaluated transcriptional in the retina of the zebrafish as photoreceptors are regenerated. Albino zebrafish were dark adapted, then half were exposed to bright constant light and half were returned to normal lighting. After 72hrs of light exposure, retinal RNA was isolated and analysis of gene expression was performed using Affymetriz zebrafish gene arrays.

2009-01-13 | E-GEOD-13999 | biostudies-arrayexpress

ASCL1 induces neurogenesis in human Muller glia

Project description:In mammals, loss of retinal cells due to disease or trauma is an irreversible process which can lead to blindness. Interestingly, regeneration of retinal neurons is a well-established process in some non-mammalian vertebrates and is driven by the Muller glia (MG), which are able to re-enter the cell cycle and reprogram into neurogenic progenitors upon retinal injury or disease. Progress has been made to restore this mechanism in mammals to promote retinal regeneration: MG can be stimulated to generate new neurons in vivo in the adult mouse retina after the over-expression of the pro-neural transcription factor Ascl1. In this study, we applied the same strategy to reprogram human MG derived from fetal retina and retinal organoids into neurons. Combining scRNA-seq, scATAC-seq, Immunofluorescence, and electrophysiology we demonstrate that human MG can be reprogrammed into neurogenic cells in vitro.

2023-10-30 | GSE246169 | GEO

Cis-Regulatory Accessibility Directs Muller Glial Development and Regenerative Capacity

Project description:Diseases and damage to the retina lead to losses in retinal neurons and eventual visual impairment. Although the mammalian retina has no inherent regenerative capabilities, fish have robust regeneration from Müller glia (MG). Recently, we have shown that driving expression of Ascl1 in adult mouse MG stimulates neurogenesis similar to fish regeneration. The regeneration observed in the mouse is limited in the variety of neurons that can be derived from MG; Ascl1-expressing MG primarily generate bipolar cells. To better understand the limits of MG-based regeneration in mouse retinas, we used ATAC- and RNA-seq to compare newborn progenitors with MG. Our analysis demonstrated striking similarities between MG and progenitors, with losses in regulatory motifs for neurogenesis genes. Young MG were found to have intermediate expression profiles and accessible DNA, which is mirrored in the ability of Ascl1 to direct bipolar neurogenesis in young MG. When comparing what makes bipolar and photoreceptor cells distinct from glial cells, we find that bipolar-specific accessible regions are more frequently linked to bHLH motifs and Ascl1 binding, indicating that Ascl1 preferentially binds to bipolar regions. Overall, our analysis indicates a loss of neurogenic gene expression and motif accessibility during glial maturation that may prevent efficient reprogramming.

2020-08-19 | GSE137318 | GEO

Direct induction of retinal ganglion cell-like neurons

Project description:Mouse embryonic fibroblasts were reprogrammed into retinal ganglion cell-like neurons by overexpressing Ascl1/Brn3b/Isl1 transcription factor combination in 13 days.

2020-09-30 | GSE140128 | GEO

Transcription profiling by array of adult zebrafish control and post-lesion retina to investigate the molecular determinants of retinal regeneration in adult vertebrate

Project description:Purpose: Investigate the molecular determinants of retinal regeneration in adult vertebrates by analyzing the gene expression profiles of control and post-lesion retina of adult zebrafish, a system that regenerates following injury. Methods: Gene expression profiles of zebrafish retina and brain were determined with DNA microarray, RT-PCR, and real-time quantitative PCR analyses. Damaged retinas and their corresponding controls were analyzed 2-5 days post-lesion (acute injury condition) or 14 d post-lesion (cell regeneration condition). Results: Expected similarities and differences in the gene expression profile of zebrafish retina and brain were observed, confirming the applicability of the gene expression techniques. Mechanical lesion of retina triggered significant, time-dependent changes in retinal gene expression. The induced transcriptional changes were consistent with cellular phenomena known to occur, in a time-dependent manner, subsequent to retinal lesion, including cell cycle progression, axonal regeneration, and regenerative cytogenesis. Conclusions: The results indicate that retinal regeneration in adult zebrafish involves a complex set of induced, targeted changes in gene transcription, and suggest that these molecular changes underlie the ability of the adult vertebrate retina to regenerate. Keywords: time course; injury response; cellular correlation Control brain and retina (unlesioned); Control and lesioned retina (matched animals, at least n = 8 for each condition).

2005-09-16 | E-GEOD-3303 | biostudies-arrayexpress

Single cell RNA sequencing unravels the transcriptional network underlying zebrafish retina regeneration

Project description:In the lesioned zebrafish retina, Müller glia produce multipotent retinal progenitors that generate all retinal neurons, replacing lost cell types. To study the molecular mechanisms linking Müller glia reactivity to progenitor production and neuronal differentiation, we used single cell RNA sequencing of Müller glia, progenitors and regenerated progeny from uninjured and light-lesioned retinae. We discover an injury-induced Müller glia differentiation trajectory that leads into a cell population with a hybrid identity expressing marker genes of Müller glia and progenitors. A glial self-renewal and a neurogenic trajectory depart from the hybrid cell population. We further observe that neurogenic progenitors progressively differentiate to generate retinal ganglion cells first and bipolar cells last, similar to the events observed during retinal development. Our work provides a comprehensive description of Müller glia and progenitor transcriptional changes and fate decisions in the regenerating retina, which are key to tailor cell differentiation and replacement therapies for retinal dystrophies in humans.

2023-03-03 | GSE226373 | GEO

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