One of the most intriguing questions in biology discusses why some animals can regenerate their major body parts, such as hearts and limbs, and others cannot. A new study led by Dr. James Godwin from the MDI Biological Laboratory suggests that the innate immune system could be the answer.
Secrets revealed in salamander study
A recent study investigating heart regeneration in the axolotl, a Mexican salamander, has shed light on how this species achieves an astounding ability to regenerate. The researchers found that tissue regeneration and the formation of new heart muscle tissue in the axolotl after inducing a heart attack depends on macrophages being present at the injury site.
The study showed that when macrophage numbers are low, permanent scar tissue forms, blocking the regeneration of new healthy tissue. When macrophages are present in sufficient numbers, healthy regeneration occurs.
The aim of this research is to find ways to promote scar-free healing in humans following a heart attack. They seek to do this by either finding drugs derived from the molecules that macrophages secrete to heal tissue or to directly activate macrophage populations themselves to facilitate healing.
If fibrosis (scarring) can be prevented in the same way that salamanders avoid it, this may allow humans to regenerate damaged heart tissue in the same way. It is not clear if fibrosis is the only thing preventing regeneration at this point in time, but, if we are lucky, preventing scarring might be enough to unlock our own potential to regenerate.
Turning established thinking upside down
It has been the view in regenerative medicine that the biggest hurdle to overcome in heart regeneration is the lack of cardiomyocyte (cardiac muscle cell) proliferation. However, the researchers found that cardiomyocyte proliferation is not the only determinant in heart regeneration. The signalling factors secreted by macrophages are also very important in tissue regeneration.
Indeed, the role of macrophages has been in the spotlight recently, as researchers have altered their behaviour to encourage them to become healing macrophages rather than pro-inflammatory ones, thereby facilitating tissue regeneration. A number of studies have been experimenting with this, and we talk about that here, here and here.
The leading cause of death worldwide
Heart disease causes disability, is the leading cause of death worldwide, and can be directly linked to scarring of the heart. When a person suffers a non-fatal heart attack, scar tissue forms at the injury site; this scar tissue limits the extent of tissue damage in the short term, but its presence hinders regeneration and reduces the heart’s ability to pump blood in the long term. This ultimately leads to disability and heart failure.
Finding ways to activate macrophages or emulate the factors they secrete is a potential path to treating heart disease and, indeed, other injuries resulting in fibrotic tissue.
The research has even wider potential than this; if we can unlock the dormant potential for regeneration in humans that the salamander has by suppressing scarring, this also has potential for the regeneration of tissues and organs lost due to traumatic injury.
Understanding regeneration in animals is the key to creating therapies in humans
The MDI Biological Laboratory holds that in order to develop effective regenerative medicine therapies for humans, we must first understand how regeneration works in animals such as salamanders. To that end, this laboratory has been studying a variety of animals that demonstrate robust regenerative abilities.
The findings of this new study are a validation of this approach, and the lab is currently screening a library of molecules to find ones capable of triggering the dormant genetic pathways for regeneration in humans. In the past year and a half, the lab has discovered three drug candidates with regenerative potential.
This new study follows on from an earlier study that showed macrophages also play a key role in the regeneration of lost limbs.
The next step for the team is to study how macrophages in salamanders, mice and humans function and compare them. Ultimately, Godwin and his team want to see why macrophages produced in adult mice and humans do not suppress scarring like the salamander does. Once that is understood, the final move will be to identify the genetic pathways and ways to activate them that would then allow humans to regenerate damaged heart tissue in the same way.
Humans have the same genetic machinery of salamanders and other animals that can regenerate damaged tissue at an amazing level. The difference is that in humans, this machinery lies dormant, and we do not benefit from it. If we can activate this dormant machinery by either directly manipulating macrophage types and numbers or by emulating their secreted molecules, we have the basis for therapies that could potentially prevent heart failure.
Our understanding is growing by each passing month, and it seems to be only a matter of time before we crack the code and unlock regeneration in humans.
 Godwin, J. W., Debuque, R., Salimova, E., & Rosenthal, N. A. (2017). Heart regeneration in the salamander relies on macrophage-mediated control of fibroblast activation and the extracellular landscape. NPJ Regenerative Medicine, 2, 1.
 Godwin, J. W., Pinto, A. R., & Rosenthal, N. A. (2013). Macrophages are required for adult salamander limb regeneration. Proceedings of the National Academy of Sciences, 110(23), 9415-9420.