When humans and mammals lose a finger, arm, or leg, the best hope for now is advanced prosthetics, which does provide regained function. But the holy grail of treatment would be limb regeneration, where the site of a lost appendage is treated with a chemical for the regrowth of a fully formed limb. We see this in the animal kingdom, where salamanders and other reptiles can lose their tail or a leg and have it seamlessly grow back. The only organ that regenerates in humans as such is the liver, the resilience of which is necessary in order to process so many toxins. The liver can grow back to full size after two-thirds of it is taken for an organ donation.

A lot of research has focused on salamanders and their ability to regenerate fully functional limbs. While most of the research has focused on genetics, working to tease out if there are specific genes that people don't have or have inactivated that help limb regeneration, little work has been done on the role of the immune system. A research group from the Australian Regenerative Medicine Institute (ARMI) at Monash University has looked into a type of immune cell that is important in inflammation, but also in clearance of dead and infected cells for its role in limb regeneration and has published their findings in the Proceedings of the National Academy of Sciences.

They found that when they removed macrophages from salamanders, they were unable to regenerate limbs. "Previously, we thought that macrophages were negative for regeneration, and this research shows that that's not the case - if the macrophages are not present in the early phases of healing, regeneration does not occur," Dr. James Godwin, lead researcher on the project, said.

The amazing thing about the regeneration of tissue and limbs on salamanders is that they become repaired with no scar tissue. Scientist, doctors, and patients see this line of research as key in repairing damage from untreatable conditions such as spinal cord injuries, limb loss, heart disease, and certain liver diseases such as hepatitis where the liver is unable to regenerate and scar tissue, or fibrosis, forms. When scar tissue is present, it impedes the functioning of an organ. Heart scar tissue, for instance, is not cardiac muscle and hurts the heart's ability to pump blood. SImilarly, spinal cord scar tissue does not transmit nerve impulses, making it a factor in paralysis.

"Now, we need to find out exactly how these macrophages are contributing to regeneration. Down the road, this could lead to therapies that tweak the human immune system down a more regenerative pathway," Dr. Godwin continued.

Children up to the age of 10 can regrow the tips of their fingers within a month of being cut off in accidents. This supports the idea that stem cells also play an important role in human tissue regeneration, as children still have a large pool of stem cells in their systems compared to adults. Research is currently zeroing in on the keys to unlocking this biological mystery and helping people to heal better. 

Recently, a type of mouse that is used to study autoimmune diseases was found to have remarkable skin healing abilities because of a genetic mutation. Also published in PNAS, the report out of the Whistar Institute at MIT found, by accident, that a certain strain of mice had a remarkable ability to regenerate skin. Researchers typically poke a hole in the ear of mice to number them for experiments, but the research group of Dr. Ellen Heber-Katz found that some mice that they had used for an experiment had no ear punches weeks into an experiment, even though they had been numbered. This esssentially ruined the experiment, but led the research group on a more than decade long journey into the science of regenerative medicine. It took more than 12 years to narrow down the gene, called p21, that allows the mice to heal from such trauma.   

 

MRL
MRL mice with a p21 mutation can regenerate ear punch holes, unlike regular mice. (left wild type normal mice, right mutant mice) Credit:Wistar Institute

 

Source: Bedelbaeva K, Snyder A, Gourevitch D, et al. Lack of p21 expression links cell cycle control and appendage regeneration in mice. PNAS. 2010.

Godwin J, Pinto A,  Rosenthal N. Macrophages are required for adult salamander limb regeneration PNAS 2013 ; published ahead of print May 20, 2013