Researchers have developed a way for chemically modified glass to transform UV light into visible light, improving visual performance in zebrafish. Terbium and europium, known for enhancing visible light absorption, were applied as coatings on the glass to further boost visual performance.

The Hyde lab is currently investigating how Muller glial cells, a form of retinal stem cell, regenerate lost neurons in zebrafish retinas. Their research could lead to methods of stimulating human Muller glial cells for curing age-related macular degeneration and glaucoma blinding diseases.

1. Regeneration of Photoreceptors

Researchers have recently made an exciting discovery: that the retina of zebrafish fish possesses an astounding capacity for regeneration that allows it to replace lost photoreceptors, or light-sensitive cells responsible for sensing visual stimuli. By suppressing specific micro-RNA, they discovered that Muller glia cells within its retina transform into stem cells which then differentiate and regenerate rod and cone photoreceptors lost through age related macular degeneration or retinitis pigmentosa disease regrowth, opening doors for potential cures for blinding conditions like age related macular degeneration or retinitis pigmentosa disease treatment options. This could open new avenues towards finding cures to blinding diseases like age related macular degeneration or retinitis pigmentosa disease treatment solutions.

Retinal regeneration is a complex process involving three distinct cell types. Regeneration occurs as a result of loss of photoreceptors, leading to degeneration that stimulates Muller glial cells to regenerate new retinal cells which take over from damaged photoreceptors. Regeneration begins once photoreceptor loss has taken place and degeneration activates Muller glial cells to generate new retinal cells that take on their functions in place of damaged photoreceptors.

Transdifferentiation has been observed in amphibians, fish, birds, and mammals; its prevalence declines with retina maturity. Researchers in this study utilized high intensity light to damage zebrafish retinas with photoreceptor degeneration; however, Muller glial cells quickly transformed into stem cells to regenerate new photoreceptor cells to restore lost photoreceptors.

Researchers transplanted GFP-expressing cells from transgenic mice in which all rod photoreceptors are green into the subretinal space of wild-type mice. The transplanted cells successfully integrated into their host retina, re-express rhodopsin and other markers of mature rod photoreceptors, and showed normal synaptic connections with host bipolar cells. They discovered that integration efficiency is highly dependent on tight junction integrity between glial cells in the host retina forming outer limiting membrane tight junction integrity; using ZO-1 siRNA or chondroitinase ABC to increase this integrity they could increase integration efficiency significantly.

Researchers believe this to be the first demonstration of regenerative retinal therapy in mammalian animals. Though their retinas’ potential to regenerate is limited, this research provides an essential first step to finding cures for many blinding diseases that result from lack of photoreceptors; such as genetically inherited blinding conditions like Retinitis Pigosa, Glaucoma, and Age-Related Macular Degeneration.

2. Regeneration of Retinal Ganglion Cells

Loss of retinal ganglion cells (RGCs) is a hallmark of eye diseases such as glaucoma and macular degeneration, with RGCs lacking self-repair ability in humans only proliferating following injury; in contrast, RGCs in zebrafish possess the unique capability of regeneration on their own in response to trauma or experimentally-induced degeneration through transdifferentiation of one cell type into another cell type.

Amphibians, fish, birds and mammals have demonstrated various degrees of retinal regenerative capacity in early development; its capability decreases with maturity of organism. Current avenues of research aim to identify factors which initiate these processes and uncover ways in which human retinas could benefit from increased regeneration potential.

Recent studies have challenged previous beliefs that posthatch chicken retina CMZs were inactive; recent evidence has demonstrated otherwise through insulin IGF-1 and sonic hedgehog combination treatment to induce proliferation in these cells (Fischer and Reh 2000). Gene transfer can also reactivate this pathway; such reprogramming may prove useful in treating mammalian eyes suffering from retinal degenerative disorders like glaucoma and macular degeneration by activating regeneration pathways to restore their regenerative capabilities.

Scientists are developing protocols to directly reprogram human glial fibroblasts into functional retinal neurons for regeneration purposes. These techniques will play an integral role in future therapeutic interventions to restore or replace lost axons and synapses within the retina. Researchers recently discovered that Ascl1a is necessary for the proliferation of glial fibroblasts in zebrafish and activating this gene can initiate similar regenerative responses after eye injuries or chemical toxicity in mammalian MGs, providing insight into an effective cell replacement therapy that could treat diseases like glaucoma and macular degeneration. This information will be crucial in creating safe cell therapy to treat eye conditions like glaucoma and macular disease.

3. Regeneration of Muller Glia Cells

Researchers are studying zebrafish to understand how to induce endogenous regeneration of retinal cells – an approach to treating age-related macular degeneration and Leber congenital amaurosis. These diseases are largely caused by photoreceptor loss in the retina, and current treatments involve reinfusing new stem cells to replace those lost. Scientists have tried transplanting induced pluripotent stem cells (iPSC) or embryonic stem cells (ESC) into damaged retinas before, with mixed results. But researchers from Dr. HE Jie’s lab at the Institute of Neuroscience Center for Excellence in Brain Science and Intelligence Technology of Chinese Academy of Sciences found that retinal Muller glia can regenerate into functional neurons after being transplanted – this suggests hope of further restoration for sight loss patients.

This research seeks to make testing treatments for vision-restoring stem cell transplants simpler, particularly among human patients. To do this, a team created a zebrafish model which quickly evaluates how drugs affect transplanted stem cells’ ability to regenerate into functional eye tissue after being transplanted into them. They injected drugs directly into each fish before measuring how well their cells integrate with retina.

The zebrafish model is an invaluable way to evaluate stem cell safety without anesthesia and is simple to replicate. The team hopes that one day a similar method may be developed in humans that would enable testing more drugs at lower doses and faster rates than traditional animal-based models.

Zebrafish provide an ideal model organism to study endogenous regenerative mechanisms due to their remarkable regeneration capabilities. If a researcher were to remove part of a heart from a zebrafish, it would regrow in weeks! Scientists are now working with Zebrafish researchers and studying their genes that promote this process and how humans might activate its equivalent mechanism.

Early in retinal development, Muller glia are multipotent cells capable of creating all types of neurons in the retina. Following injury however, Muller glia can lose this multipotency and return to cell division as progenitor cells which then give rise to rod or cone progenitors – this reprogramming of Muller glia into retinal progenitors has been observed both in fish central retina regeneration as well as chick embryo development.

4. Regeneration of Retinal Neurons

Human glaucoma and macular degeneration cause photoreceptors and retinal ganglion cells to degenerate over time, leaving only their repair mechanisms to restore vision in patients suffering from these disorders. Current avenues of research seek to restore stem cell characteristics in support cells or generate replacement cells and transplant them back into diseased retinas for restoration of sight.

Zebrafish have an advantage in these efforts because of their unique ability to regenerate entire retinas – unlike mammalian species – unlike mammalian species. This provides them with a valuable model for understanding how human cells may regenerate more effectively to replace lost tissues and restore vision.

Researchers used high-intensity light to put their hypothesis to the test by damaging zebrafish retinas with intense lighting. Although damage resulted in the loss of cone photoreceptors, retinas did not degenerate like they would for humans with macular degeneration; instead they showed partial regeneration through environmental constraints on regeneration; researchers were then able to pinpoint exactly which mechanism was limiting full recovery.

The team also demonstrated that Muller glial cells, which normally form the outer limiting membrane of retina, reenter cell cycle following injury to generate new Muller glia cells and axons that integrate into retinal circuitry. Notch signaling pathway plays a vital role in this reentry into cell cycle process and its inhibition enables Muller glia cells to remain in an adaptable cellular state necessary for integration of retinal progenitors into synaptic networks that define retina function.

Utilizing the transparency of an early zebrafish embryo, researchers were able to examine over 1000 individual cells in vivo and identified six major neurogenic lineages that produce all six retinal neurons (retinal ganglion cell, amacrine cell, horizontal cell, bipolar cell and photoreceptor) via transcription factor targeting. By targeting expression of one transcription factor to these cell types directly, their team demonstrated efficient lineage-dependent reprogramming within vertebrates.

Research results were recently published in Journal of Cell Biology on July 23. The team’s study demonstrated that zebrafish RPE cells could be easily reprogramed to create specific neuron types, providing proof-of-concept for such reprogramming in human macular degeneration models such as Stargardt disease caused by mutations in ABCA4.