A fresh start

Gene Regulation, Stem Cells and Cancer

Researchers from the CRG have discovered that reprogramming and regenerating retinal neurones is possible

When she decided to become a scientist, Daniel Sanges was aware she would have to reinvent herself every few years throughout her career. A postdoctoral researcher at the Centre for Genomic Regulation, she has been working with Pia Cosma, head of the Reprogramming and Regeneration group, since 2010. Now, when this course ends, she will have to pack up and move to another city, country or maybe even continent.

“That’s the life of a scientist and although sometimes it can be hard to start again in a new place, it enables you to continuously enrich your knowledge. In Italy, I learnt a lot about a specific eye illness and here at the CRG I have looked deeper into cell reprogramming and regeneration. It’s fascinating! And I want to continue learning more about the basic principles that regulate life”, explains this young molecular biologist.

Sanges highlights the fact that we often forget about the plasticity of both our brain and our whole body. For her, we all have the ability to, at a certain moment in our lives, reinvent ourselves, make a fresh start, change and to do whatever we want or need to do. “We have the capacity to reprogramme our lives”.

Just as cells do, if stimulated in the proper way. Together with Cosma, an ICREA research professor, Sanges has managed to reprogramme neurones in order to give them new life, regenerating the damaged retina of mice: a crucial step towards regenerative medicine.

A pathway named Wnt

The first embryonic stem cells were obtained in 1988 and since then scientists have tried to use them for regenerating organs and tissues. Nevertheless, until now research had produced few results. A couple of years ago Pia Cosma and Daniela Sanges started investigating one type of reprogramming mechanism, called cell fusion, consisting of merging two different kinds of cells. In this case, they introduced bone marrow stem cells into damaged retinal neurones. They observed that both cells fused and they discovered that the new hybrid obtained could differentiate into diverse types of neurones.

“We saw that these new hybrids, or undifferentiated cells, fused with the retinal neurones and acquired the ability to regenerate tissue”, explains Cosma, group leader at the CRG.

At first, Cosma and Sanges were interested in understanding whether it was possible to regenerate the nervous tissue and they focused on the retina, as it is part of the central nervous system and an extremely simple and accessible tissue, with a very weak response to transplanted cells.

They used bone marrow cells because these circulate in the blood of every adult and do not involve either the ethical or technical problems presented by embryonic stem cells. Moreover, previous research showed they could fuse with other cells and suggested they could have the potential to regenerate tissues.

Their discovery, published in the prestigious journal Cell Reports, is the first time regeneration of the retina and reprogramming of its neurones through in vivo cell fusion has been achieved. And the key for doing so has been a pathway known as Wnt, a chemical cascade inside the cell that can trigger both reprogramming and regeneration.

“This mechanism allows lower organisms to regenerate a part of their bodies. If you cut a limb or a fin from a frog, fish, or lizard, it will regrow. But we mammals have lost this potential control through the Wnt signalling activation pathway. We would now like to continue studying how to reactivate this endogenous repair mechanism in mammals”, announces Cosma.

In humans, skin is a regenerative tissue controlled by Wnt signalling, as is the liver, which is in fact the only organ you can cut a piece off and after a certain time will regrow. Nevertheless, our regenerative potential is very limited and this is what Cosma’s research group want to study from now on.

A treatment for certain eye illnesses

In this work, the CRG researchers focused on the degeneration of ganglion cells, a class of neurones located near the inner surface of the retina of the eye that have a long axon extending into the brain; they receive visual information from photoreceptors and transmit it to several regions of the brain. When degeneration of these neurones occurs, it affects vision and can cause blindness, as in glaucoma, diabetic retinopathy or pigmentary rethinopathy.

They have already obtained a patent for this discovery and have an agreement with Ferrer International to develop a therapy based on their results. “They did a preclinical study in mice, to confirm the safety of the technique, and we hope to start doing clinical trials with patients by the end of 2015”, affirms Cosma, who adds: “cells will be activated with the Wnt signalling and then transplanted into the patients’ eyes, if all the preclinical work is successful.”

The discovery is important not only because of the potential medical applications for retinal regeneration, but also for the possible regeneration of other more complex nervous tissues.

Reference work:

Sanges D, Romo N, Simonte G, Di Vicino U, Tahoces AD, Fernández E, Cosma MP.
“Wnt/β-catenin signaling triggers neuron reprogramming and regeneration in the mouse retina.”
Cell Rep, 4(2):271-86 (2013).