Regeneration – the ability to recreate lost or damaged cells, tissues, organs or even limbs – has a limited capacity in mammals.
While skin and hair cells constantly renew themselves, unlike a newt, if a human loses a leg, there is no second chance.
But the discovery of a strain of mouse, the Murphy Roths Large (MRL), with remarkable regenerative capabilities has opened up the possibility that those properties could be transferred to other mammals.
Professor Ellen Heber-Katz, a scientist from the Wistar Institute in Philadelphia, US, was part of the way through an immunological study when she first stumbled across the MRL mouse’s amazing abilities.
She was looking at the effects of a drug, and had marked the mice that had received the drug by punching a small hole in their ear to distinguish them from those who had not.
"I went upstairs and I looked in the cage, but none of the mice were marked," she said. "I looked at them and thought: ‘what’s happened?’ I thought the post doc hadn’t done the experiment.
"So we did it again, and we watched them, and there it was – the holes had closed up. I thought, ‘Oh my God, this is just amazing’."
When they looked closer they saw that there had been DNA synthesis, cell proliferation and both cartilage and new hair follicles had also grown.
Digit regrowth
The MRL mouse has been used in research for years – mostly as a model for autoimmune diseases because the genetic mutations they carry mean they have a lupus-like disease.
But the accidental discovery by Professor Heber-Katz of this rapid regrowth opened up a new avenue of research.
After talking to colleagues and realising that this kind of healing had never been seen before in a mouse, Professor Heber-Katz’s team switched from immunology to regeneration and began to look at the mouse to see the extent of these regenerative properties.
"Everything we have looked at has been different to what our control mouse looks like," said Professor Heber-Katz.
When the team used a cold probe to make a small injury to the heart of the MRL mice they found that the tissue regenerated and there was no scarring.
When they examined what happened after spinal cord injury, again they found cell re-growth and little scarring.
The MRL mouse has even been shown to have some digit regrowth.
"It is known that if you cut off the digit tip in mice it always seems to come back; but if you cut any further, you get no growth.
"We did that in the MRL mouse and there is a blastema [area of growth] that forms, there is DNA synthesis and cell proliferation, and we also think that maybe there is the beginnings of a joint that is formed. I must say that we have not seen the whole digit grow back"
The membrane factor
Professor Heber-Katz has begun to look at why the MRL mouse has such unusual healing abilities.
"This animal has an unusual ability to show cell proliferation and lack of scarring which I think are two key elements to why we don’t regenerate."
She believes that one of the factors that blocks regeneration in most mammals is a membrane that forms as the body starts to repair itself.
She points out that when amphibians regenerate their limbs, a basement membrane does not form, but if you promote the growth of this membrane, then it seems to stop cell growth and causes scarring.
When the team looked at the formation of the membrane in the ears of MRL mice, they found that it did form initially, but disappeared soon after and then cell growth begins.
Further work has shown that two genes, mmp9 and mmp2, may be implicated.
The team have also carried out an interesting experiment whereby they injected foetal liver stem cells from a MRL mouse into the tail vein of a non-healing mouse, and then a month later caused a small injury to the heart.
"We found that you get islands of cardiomyocytes [heart muscle cells] that are forming in these mice. If you look at the degree of scar formation, you don’t see any scars."
They then transferred foetal liver stem cells from the non-healing mice to the MRL mice and saw that the mice formed a lot of scar tissue and little cardiomyocyte island formation.
"If we can deplete the cell factor causing scarring, then we might be able to enhance the regenerative ability of mammals in general."
Genetic mapping
Professor Heber-Katz’s team are now looking to see if they can breed mice have the regenerative capabilities but do not carry autoimmune disease.
So far they have managed to create mice that can regenerate ear holes, but not mice that can do that and repair heart tissue.
"The genes involved in heart regeneration are no doubt overlapping with the ear hole closing ones, but it requires more or some different genes."
The team are now in the process of mapping genes to try and shed more light upon the genetic combinations that may be at the root of the mouse’s regenerative process.
"It is a long term project, but once we know the molecules involved we can the try to modify them to see if we can get this kind of response in mammals"
The complicated nature of mammals means that we might still be a long way off the day when mammals can begin to display MRL-like regenerative properties, but Heber-Katz says the mouse could provide the first step on the path.
"You never really know when you’re going to find the answer – it could be very far off or it could be very close. You just don’t know."
"The mouse definitely is not perfect, it is not like a newt in terms of its powers of regeneration, but it does do a lot of things that other mammals don’t do, and therefore it’s definitely an important thing to study."
