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“Awakening” the Regenerative Potential of Human Retina with Cell Fusion

Fusing adult stem with special stem cells in the retina could be a potential therapeutic strategy to promote retina rescue and regeneration and treat retinal damage and visual impairment.

According to the World Health Organization, at least 2.2 billion people worldwide suffer from near or distance vision impairment. About 1 billion of these cases include those with moderate or severe distance vision impairment or blindness due to cataract, corneal opacities, diabetic retinopathy, glaucoma, trachoma, unaddressed presbyopia, and untreated refractive error. As it stands, correcting visual impairment due to retinal injury or disease remains to be an unmet medical need.

In a recent study led by ICREA Research Professor Pia Cosma at the Centre for Genomic Regulation (CRG) in Barcelona, scientists have reported that fusing human retinal cells with adult stem cells could be a potential therapeutic strategy to treat retinal damage and visual impairment. Although previously thought to be the preserve of cold-blood vertebrates, these hybrid cells appear to awaken the regenerative potential of human retinal tissues.

Cell fusion takes place when two different cells combine into one single entity. While this phenomenon has been recognised to be a possible mechanism contributing to tissue regeneration, cell fusion is rare in humans and has only been consistently detected in the brain, gastrointestinal tract, and liver. However, CRG researchers have found that cell fusion events can also occur in the human retina.

With this discovery, the researchers were keen to investigate Müller glia cells, which had been recently reported to not only help maintain the structure and function of the retina but also retain intrinsic stem cell features. Over the past few years, the researchers have demonstrated the potential therapeutic use of cell fusion-derived hybrids in models of retinal disease, suggesting that cell fusion contributes to the regeneration of retinal neurons.

To determine whether cell fusion events could differentiate into cells that turn into neurons, thereby showing potential for tissue regeneration, Cosma and colleagues fused Müller glia with adult stem cells derived from human adipose tissue or bone marrow. If successful, the researchers hypothesised that fusion-mediated regeneration using adult stem cells could be a treatment for human retinal dystrophies.

“We were able to carry out cell fusion in vitro, creating hybrid cells. Importantly, the process was more efficient in the presence of a chemical signal transmitted from the retina in response to damage, resulting in rates of hybridisation increasing two-fold. This gave us an important clue for the role of cell fusion in the retina,” explained Sergi Bonilla, postdoctoral researcher at the CRG at the time of publication and first author of the study.

When the hybrid cells were injected into growing retinal organoids, it was observed that the hybrid cells successfully engrafted into the tissue and differentiated into cells that closely resemble ganglion cells, a type of neuron essential for vision.

“Our findings are important because they show that the Müller Glia in the human retina have the potential to regenerate neurons,” said Research Prof. Cosma. “Salamanders and fish can repair damage caused to the retina thanks to their Müller glia, which differentiate into neurons that rescue or replace damaged neurons. Mammalian Müller glia have lost this regenerative capacity, which means retinal damage or degradation can lead to visual impairment for life. Our findings bring us one step closer to recovering this ability.”

Having demonstrated a new potential use of hybrid cells, their findings are expected to advance stem-cell mediated therapy for human retina rescue and generation. However, the scientists cautioned that further research is needed before they can begin to develop any potential treatments. They must first uncover why hybrid cells – with four complete cetes of chromosomes – do not result in chromosomal instability and cancer development. One reason may be that the retina has a mechanism for regulating chromosome segregation similar to the liver, which possesses tetraploid cells that act as a genetic reservoir and undergo mitosis in response to stress and injury. [APBN]

Source: Bonilla-Pons et al. (2022). Müller glia fused with adult stem cells undergo neural differentiation in human retinal models. eBioMedicine, 77, 103914.