Can we repair damaged retina like zebrafish do?

By the action of a particular gene, the specilaised cells transform into multipotent stem cells, which aids in regeneration, says Rajesh Ramachandran (centre)  

In stark contrast to mammals, the zebrafish has the ability to completely regenerate its retina and restore vision after an injury. Researchers from Indian Institute of Science Education and Research (IISER) Mohali, have decoded the signals and genes behind this tremendous feat and hope to uncover valuable clues as to why we humans fail at such regeneration.

A particular signalling system — sonic hedgehog (Shh) — in zebrafish has been previously reported to aid in developmental and tissue regeneration activities. To decipher the influence of Shh signalling on retina regeneration, the researchers first inhibited its function. They found that impairing this signal made 90% of the zebrafish embryo exhibit a birth defect called cyclopia. Cyclopia is also seen in humans, where there is a single median eye or a partially divided eye. Detailed understanding of this signalling may provide insights into the rare defect. Since this signalling is also responsible for retina regeneration in zebrafish, the researchers are trying to understand why the signalling does not bring about retina regeneration in humans.

They performed whole retina RNA sequencing at various time points post-retinal injury to the zebrafish eye. Several genes (zic2b, foxn4, mmp9) were found to be upregulated through Shh signalling. Zic2b and foxn4 are essential components for development and tissue regeneration, whereas mmp9 is an enzyme which makes the environment congenial for freshly formed cells. Individual knockdowns of these genes also revealed that these are indeed essential for normal retina regeneration.

The researchers also showed the role of a microRNA (let-7) which is regulated through a particular gene (Lin28a) which allows normal Shh signalling during the retina regeneration process. “During an injury, you need the proliferation of cells that let-7 is capable of blocking. So Lin28a steps in action, clears or scavenges let-7 and allows differentiated cells to be transformed into multipotent stem cells, which aid in regeneration,” explains Rajesh Ramachandran from the Department of Biological Sciences at the Institute and corresponding author of the work published in the journal Cell Reports.

Mice models

They further carried out studies on mice models by injecting the protein. “Shh protein can easily bind to its respective receptor and turn on the signalling pathway after an acute retinal injury,” says Simran Kaur, PhD scholar and first author of the work. “Though there was increased proliferation and upregulation of the genes, no regeneration of the retina was seen in mice.”

“Although we have understood the signals and genes behind the regeneration, the whole pathway and network need to be unravelled before trying it out in the mammalian system,” adds Prof. Rajesh.

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Printable version | Jan 28, 2021 1:40:08 AM |

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