Muller glia originate from neuroepithelium and are the principal glial cells in the retina. During retinal development, Muller glia are one of the last cell types to be born. In lower vertebrates, such as zebrafish, Muller glia possess a remarkable capacity for retinal regeneration following various forms of injury through a reprogramming process in which endogenous Muller glia proliferate and differentiate into all types of retinal cells. In mammals, Muller glia become reactive in response to damage to protect or to further impair retinal function. Although mammalian Muller 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 Muller glia reprogramming. Progress has been made in triggering Muller glia to reprogram and generate functional neurons to restore vision in mammals indicating that Muller 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 Muller glia reprogramming in mammals.

Müller Glia-Mediated Retinal Regeneration.

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Turning lead into gold: reprogramming retinal cells to cure blindness.

Regenerative and restorative medicine for eye disease

A stem cell aging framework, from mechanisms to interventions.

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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On the Generation and Regeneration of Retinal Ganglion Cells.

Single-cell transcriptomics of adult macaque hippocampus reveals neural precursor cell populations

Glaucoma and other optic neuropathies affect millions of people worldwide, ultimately causing progressive and irreversible degeneration of retinal ganglion cells (RGCs) and blindness. Previous research into cell replacement therapy of these neurodegenerative diseases has been stalled due to the incapability for grafted RGCs to integrate into the retina and project properly along the long visual pathway. In vivo RGC regeneration would be a promising alternative approach but mammalian retinas lack regenerative capacity. It therefore has long been a great challenge to regenerate functional and properly projecting RGCs for vision restoration in mammals. Here we show that the transcription factors (TFs) Math5 and Brn3b together are able to reprogram mature mouse Muller glia (MG) into RGCs. The reprogrammed RGCs extend long axons that make appropriate intra-retinal and extra-retinal projections through the entire visual pathway to innervate both image-forming and non-image-forming brain targets. They exhibit typical neuronal electrophysiological properties and improve visual responses in RGC loss mouse models. Together, our data provide evidence that mammalian MG can be reprogrammed by defined TFs to achieve in vivo regeneration of functional RGCs as well as a promising new therapeutic approach to restore vision to patients with glaucoma and other optic neuropathies.

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In vivo Regeneration of Ganglion Cells for Vision Restoration in Mammalian Retinas

Glaucoma and optic neuropathies cause progressive and irreversible degeneration of retinal ganglion cells (RGCs) and the optic nerve and are currently without any effective treatment. Previous research into cell replacement therapy of these neurodegenerative diseases has been stalled due to the limited capability for grafted RGCs to integrate into the retina and project properly along the long visual pathway to reach their brain targets. In vivo RGC regeneration would be a promising alternative approach but mammalian retinas lack regenerative capacity even though cold-blood vertebrates such as zebrafish have the full capacity to regenerate a damaged retina using Muller glia (MG) as retinal stem cells. Nevertheless, mammalian MG undergo limited neurogenesis when stimulated by retinal injury. Therefore, a fundamental question that remains to be answered is whether MG can be induced to efficiently regenerate functional RGCs for vision restoration in mammals. Here we show that without stimulating proliferation, the transcription factor (TF) Math5 together with a Brn3 TF family member are able to reprogram mature mouse MG into RGCs with exceedingly high efficiency while either alone has no or limited capacity. The reprogrammed RGCs extend long axons that make appropriate intra-retinal and extra-retinal projections through the entire visual pathway including the optic nerve, optic chiasm and optic tract to innervate both image-forming and non-image-forming brain targets. They exhibit typical neuronal electrophysiological properties and improve visual responses in two glaucoma mouse models: Brn3b null mutant mice and mice with the optic nerve crushed (ONC). Together, our data provide evidence that mammalian MG can be reprogrammed by defined TFs to achieve robust in vivo regeneration of functional RGCs as well as a promising new therapeutic approach to restore vision to patients with glaucoma and other optic neuropathies.

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Wanjing Huang

Papers

Single-cell transcriptomics of adult macaque hippocampus reveals neural precursor cell populations

Single-cell transcriptomics of adult macaque hippocampus reveals neural precursor cell populations

In vivo Regeneration of Ganglion Cells for Vision Restoration in Mammalian Retinas

Directed robust generation of functional retinal ganglion cells from Müller glia

Linking transcriptomes with morphological and functional phenotypes in mammalian retinal ganglion cells.