Regeneration: what does it mean, and how does it work?

Some parts of our bodies can repair themselves quite well after injury, but others don’t repair at all. We certainly can’t regrow a whole leg or arm, but some animals CAN regrow – or regenerate – whole body parts. So what can we learn from these regenerative animals?

What do we know?

Salamanders, flatworms, and a number of other species can regrow damaged or missing body parts. This is regeneration.

Some human organs, like the liver and skin, also regenerate when they are damaged.

Regeneration can happen in many different ways, using pluripotent or tissue-specific stem cells. Some regeneration happens without stem cells at all (e.g. the regeneration of zebrafish hearts).

Studying regeneration in these species will help us understand how the human body heals and repairs itself, and why it fails to do so in some contexts. This could help researchers develop regenerative therapies to help the human body heal more fully.

What are researchers investigating?

Researchers are investigating many aspects of regeneration, from the signals that turn on regenerative processes, to why stem cells in humans don’t regenerate the way other animals do.

Many scientists are interested in understanding how a blastema is formed: an accumulation of regenerative cells that forms at the point of tissue damage, that goes on to rebuild the missing body part.

What are the challenges?

Studies in animals like salamanders are also attempting to determine how these regenerative cells know what parts of the body need to be regrown, and where they are in the body’s ‘map’, two things cells in mammals don’t do.

Researchers are interested in understanding which signals turn stem cells ‘on’ when regeneration is needed, and keep them ‘off’ when they’re not needed.

Regeneration and humans

Regeneration means the regrowth of a damaged or missing organ part from the remaining tissue. As adults, humans can regenerate some organs, such as the liver. If part of the liver is lost to disease or injury, the liver grows back to its original size, though not its original shape. Our skin is also constantly being renewed and repaired. Unfortunately, many other human tissues don’t regenerate. A goal in regenerative medicine is to find ways to kick-start tissue regeneration in the body, or to engineer replacement tissues.

Regenerative animals

Other mammals are also capable of regeneration in some limited contexts, like humans. However, there are many animals that can regenerate complex body parts with full function and almost perfect form after injury, or even amputation. Invertebrates (animals without a spinal cord) such as the flatworm or planarian can regenerate their heads from a piece of their tail, their tails from a piece of their head – and both a head and a tail from a piece without either!

Among vertebrates (animals with a spinal cord), fish can regenerate parts of the brain, eye, kidney, heart and fins. Frogs can regenerate the limb, tail, brain and eye tissue as tadpoles, but not as adults. And salamanders can regenerate almost any body part and organ - including entire limbs, heart, tail, brain, lungs, eye tissues, kidney, brain and spinal cord throughout life. Scientists have learned a lot about regeneration by studying these animals.

How do tissues regenerate after damage?

After amputation or injury, regenerative cells gather at the injury site in a structure called a blastema. There are different types of cells which can form the blastema and contribute to regeneration.

Pluripotent stem cells

Pluripotent stem cells are capable of self-renewing, which means they can divide to produce more of themselves. They can also become any other different type of adult cell. The process of a stem cell becoming a specific type of adult cell is called differentiation. One a cell has differentiated, it stops dividing and self-renewing.

Research on flatworms (planaria) showed that a single stem cell could regenerate a whole animal! This shows that adult planaria have pluripotent stem cells – cells that can make ALL the different cell types of the animal’s body. Several research groups are now studying how these pluripotent cells are controlled in the flatworm’s body so that they do not grow out of control or form tumours.

Adult tissue stem cells

In some animals, each tissue – such as muscle, nerve, or skin – has its own set of adult tissue stem cells, that only make the different types of cells in that particular tissue. These restricted cells are called ‘progenitors’. These cells are also capable of self-renewing, but they are restricted in what type of cells they can become. In other words, a muscle progenitor cell cannot make skin, and skin stem cells can’t make muscle. One example is the cells that regenerate a frog’s tail.

De-differentiated resident cells

In some cases, adult cells which have already differentiated can go back to being progenitor cells. From there, they are able to renew themselves or re-differentiate into adult cell types, but the type of cell they can become is still limited and tissue specific.

This was first shown in axolotl limb regeneration, and has also been shown to happen in their spinal cord. This has also been seen in heart regeneration in zebrafish, where a heart muscle cell called the cardiomyocyte divides to regrow missing heart tissue. This regeneration has also been shown to happen in newly born mouse hearts, but is quickly lost as the mice age. More research is needed to understand how differentiated cells can be made to turn back into progenitors and produce new heart tissue, and why human heart cells don’t have this ability.

So - there are multiple ways in which regenerative animals regrow their tissues. Some animals use pluripotent stem cells, which can become every type of cell. Others use tissue-specific progenitor cells to regrow each different tissue type. These cells are either already present in the tissue, or are made from cells which have already differentiated that 'go back' to being progenitors.

Multipotent or tissue-specific stem cells

How do scientists study regeneration?

Scientists wanted to investigate whether salamander regenerative cells were restricted to their original type, or could become any type of cell. But how could they find out in the lab?

The researchers labelled cells in different tissues in the salamander, like muscle and skin, with a green fluorescent marker.
They then cut off a limb and allowed it to regenerate.
They tracked where the green cells moved to as they helped to regrow the new limb. They saw that the green cells only helped to regrow their own tissue type – muscle to muscle, skin to skin, for example.

This allowed them to understand that in salamander limb regeneration, the cells are not pluripotent, but have a restricted, tissue-specific lineage.

Salamander regeneration diagram — *Salamander limb regeneration: Salamanders use tissue-specific regenerative cells to regrow damaged limbs - each stem cell can only make cells belonging to one tissue.*

What are researchers working on?

Research in different regenerative animals has shown that there are various strategies for regenerating body parts built from multiple tissues, such as muscle, nerve and skin. If we understand the principles and molecules these animals use to regenerate adult tissues, could these lessons be applied to regenerating or engineering human tissue?

By learning more about the properties of stem cells that regenerate complex body parts, scientists are learning how injuries cause these stem cells to regenerate the missing part instead of just forming scar tissue. Future research may make it possible to apply this knowledge in new kinds of medical treatments.

Pluripotent stem cells

How similar are the pluripotent stem cells of the planarian to mammalian embryonic stem cells or induced pluripotent stem cells? By studying the planarian, maybe we will gain insight into how to control human induced pluripotent stem cells for use in the clinic.

Progenitor cells

Frogs use tissue cells that may be similar to our own for regeneration, so why can they regenerate a whole limb while we form scars? Ongoing research indicates that regenerative animals keep a kind of map inside their adult tissues, telling cells where they are and what they should be. Parts of this map may have been lost in mammals, or perhaps our stem cells have lost the ability to read the map. Researchers hope to find out what exactly is missing or blocked in mammals, and whether such information can be restored to direct stem cells to take part in regeneration for medical applications.

Differentiated cells

Can we make adult, differentiated cells like heart muscle cells start dividing again, as in the zebrafish or salamander? It will be important to find out why mammalian heart cells lose this ability, and if it can be restored.

Did you know?

A young salamander can regrow a whole leg in about five weeks
The salamander can regenerate the limb, heart, tail, brain, eye tissues, kidney, brain and spinal cord throughout life
The spiny mouse is the only mammal known to regenerate complex tissues and recover from large brain injuries

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Regeneration: what does it mean, and how does it work?

What do we know?

What are researchers investigating?

What are the challenges?

Regeneration and humans

Regenerative animals

How do tissues regenerate after damage?

Pluripotent stem cells

Adult tissue stem cells

De-differentiated resident cells

How do scientists study regeneration?

What are researchers working on?

Pluripotent stem cells

Progenitor cells

Differentiated cells

Did you know?

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