Newt Legs, Heart Attacks, and Stem Cells -

Last time we discussed how induced pluripotent stem cells and embryonic stem cells might be used to treat disease. We discussed at length what these cells are and where they come from. Stem cells have captured the imagination of curious people everywhere.

We and other animals have a remarkable capacity to regenerate tissue. Rats, mice and people can lose 2/3 of their liver and grow it back in a few weeks to months. Amphibians like newts can lose an entire limb or tail and grow it back in weeks. People can lose the tip of their finger and if treatment is correct (basically do nothing) it will grow back intact. This inherent regenerative potential is more prominent in younger individuals.

Many people suffer mightily from carpal tunnel syndrome that results from inflammation of the small narrow tunnel in our wrists that allow the tendons and nerves of our fingers through to our arms. This area swells and pinches the motor nerves that control the muscles of our hands. In relatively short order the nerves begin to die and no longer transmit instructions to our fingers for playing the guitar or the piano or indeed for fastening our buttons. The result is functional paralysis of the hands and very disconcerting feelings that Mom used to call pins and needles. Eventually the hand is paralyzed and the nerves through the tunnel are well and truly dead.

A wide range of ways to treat this is extant, like massage and physical therapy or injecting steroids into the tunnel to stop the inflammation. But without question the best approach to treating this debilitating malady is to operate and dissect the mess that the inflammation made. In the process the ligaments that form the tunnel are severed and for this reason the operation is called a carpal tunnel release. And release it is. Miraculously, within a day or two the hand begins to function again and at the end of a year everything is effectively normal.

Why is this relevant here?

The pressure release at the time of the operation provides instant relief, but that cannot explain the longer slower recovery of function. The functional recovery is because the nerves are regenerating. We can only speculate that the nature of the regeneration is the result of stem cells growing into the area.

Another example is that of the very tip of the heart. On a Valentine’s Day card it would be the pointy bottom of the diagram that has come to symbolize our heart. That tip can be killed when the blood supply is compromised (like in atherosclerosis, the hardening of the arteries) where the blood vessels narrow until little blood gets through. This causes the muscle in that area to die and results in what we commonly call a heart attack. Normally, when the millions and millions of muscle cells in the heart beat in coordinated effort they pump 5 liters of blood around about 60,000 miles of blood vessels inside us. Obviously, dead heart muscle cells cannot do their job, which is to periodically and repeatedly contract. It turns out that in a very limited area of the tip of the heart, dead cells can be replaced by new living functional muscle. This replacement of cells comes from a cache of stem cells in the area that live there for our entire lives. We will see later that recruiting stem cells is something other animals, like the newt, do remarkably well, even replacing lost limbs! We have learned much from the newt and this knowledge has paved the way to insights into how stem cells in the area become recruited to heal the dead tissue without making a scar.

These caches of stem cells don’t only reside in the heart, one really interesting story about these resident stem cells involves the pancreas and the liver. These vital organs develop from a very small group of cells in the fetus in a shared location and time. They are closely related to each other in developmental terms. The liver can regenerate, but what about the pancreas.

In a series of fascinating experiments Dante Scarpelli (who at one point in his career received the keys to the city of Padua, Italy!) the pancreas was all but destroyed and yet could grow back. The really amazing thing though was that in small areas of the regenerated pancreas normal new liver was found. What is this you say? Normal liver inside the pancreas…?? Was ist da los?? It turns out there is a population of cells that reside around blood vessels in the pancreas that look like and behave like stem cells. When profound damage occurs to the organ somehow these pancreas stem cells are mobilized but they must share a heritage with liver for patches of normal liver to grow in the regenerating pancreas.

Regeneration isn’t restricted to vital organs either. Many of the genes that are important in limb regeneration are known and more are found and their involvement worked out each year. Scientists discovered that genes called Tbx4 and Tbx5 are master switches of many other genes and in the context of developing limbs make an arm different from a leg. In animals like newts, that can grow a limb back after it is amputated, these genes remain active for the life of the animal. In humans and other animals that cannot regenerate limbs these genes are turned off at birth.

Could reactivation of the developmental program they regulate increase our ability to regenerate limbs?

What can we learn about regeneration, in general, from these regeneration-competent species and how they regulate their genes?

It turns out from genetic studies in humans we learned that these genes are also important during heart development and mistakes in them cause birth defect of both the heart and the limbs.

Using stem cells to repair damaged tissue is not so new after all and our own ability to regenerate organs can be used to point the way to enhancing that potential using those remarkable stem cells. In coming years much more attention needs to be given to the basic rules of regeneration in intact organisms, including us humans, in order to improve the treatment approaches we use with stem cells.

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Originally published at

Phil Iannaccone is a Professor of Pediatrics and Pathology at Northwestern University Feinberg School of Medicine.