Stem Cell and Regenerative Medicine

Regeneration and stem cell therapy are promising aspects of regenerative medicine, however both are still at the early research stage, with a very long way to go, says Nancy Singh

Stem cell therapy (SCT) has long captured the imagination of scientists worldwide as a way of regenerative medicine. Many species, most notably amphibians and certain fish, can regenerate their body parts. The salamander regenerates its limbs, tail, upper and lower jaws, lens and retina of its eye, and its intestine! This remarkable ability is particularly pronounced in the larval stage. For this reason, larval salamanders are favourites for research on regeneration.

For years, it has been not clear whether this regeneration depends on a population of pluripotent stem cells that have resided in the animal body prepared for such events (as occurs in the hydra) or the 'de-differentiation' of specialised cells, eg muscle and cartilage cells, in the stump. The zebra fish is able to re-grow its fins, scales, spinal cord and a part of its heart. In our own backyards, we have been amazed at how lizards grow their tails back!

Mammals, too, can renew damaged parts of their body. All mammals can regenerate their liver. Deer regrow their antlers, some at the rate of two centimeters a day, said to be the fastest rate of organ growth in animals.

Salamander regenerates limbs,intestine and jaws

Zebra fish regrows fins, scales and spinal cord

In many of these cases, regeneration begins when the mature cells at the site of a wound start to 'revert' to an immature state. The clump of immature cells, known as blastema, then re-grows the missing part, perhaps by tapping into the embryogenesis programme that first formed the animal.

The blastema seems to get its instructions from the wound-site cells from which it was formed, and is quite impervious to cues from new surrounding tissue if it is transplanted. If a blastema made by sectioning a salamander's limb, at the wrist is transplanted elsewhere in the body it will still grow just a wrist and paw, while a shoulder blastema will regrow the whole limb. People, of course, cannot regrow their limbs, and do not form blastemas, so the relevance of regeneration to medicine seems remote.

But the capacity for regeneration exists in such a wide variety of species that it is unlikely to have evolved independently. In support of this notion, humans are not wholly lacking in regenerative powers. Humans are capable of repairing damage to the liver. Even after 75 per cent has been removed by surgery, the liver regains its original mass in two to three weeks. It is not certain why other organs and limbs have lost this capacity, but perhaps only the liver was damaged often enough during a lifetime to make a repair system worth the cost. Many believe that the reason is the extensive and recurring injury that the liver has been exposed to in evolution-rotten food, plant toxins and viruses.

The mechanisms of liver regeneration are poorly defined but the process is central to the success of surgical resections and live donor transplantation. Usually it relies on its own mature cells, which, like those of a blastema, possess a remarkable power to divide and multiply, even though they can only restore the organ's mass, not its original structure. "We have seen that stem cells shoot up during any kind of trauma or stress, hence we are looking for answers through traumatic diagnostics," asserts Malcolm Alison from Queen Mary University of London.

A more specific reason for thinking regeneration is not a wholly lost ability comes from genes. In an interesting study, Mark Keating, a geneticist who studied regeneration in zebra fish, identified a gene that is essential for initiating blastema formation when the fish's fin is cut. Both the genes, called fgf20, and another one he found, hsp60, also exist in humans, suggesting the genetic basis for regeneration may still be in place even though the body can no longer evoke it. If these genes exist in humans but are not switched on, perhaps some drug could be developed that stimulates them into action.

Once a blastema had been induced at some wound site in the body, regeneration researchers suggest, it might regrow the missing limb or organ with no further intervention required. The genetics of regenerating animals, like the salamander, are largely unknown.

Hence, the process of regeneration has received little attention from research biologists. Many proponents of regeneration, while conceding they have a great deal more to learn, believe SCT too may not be as close to clinical use as its advocates suggest. The basic biology of regeneration is not yet fully understood, but nor is that of stem cells. Indeed, it is rather premature to think about ways to use stem cells therapeutically. Experts say that getting stem cells to behave properly in a patient's body is difficult. "The cells may not care about your theories and behave as it desires," says Henry Young, Division of Basic Medical Sciences and Department of Pediatrics, Mercer University School of Medicine, Macon, USA, an expert in adult stem cells.

Scientists reject the idea that the blastema mechanism is the only way to repair the body's tissues. Bone marrow transplantation is a big success story on which much of the hope for stem cell therapy is pinned on. But regeneration researchers believe the bone-marrow example may be misleading because blood is not an organised tissue and the marrow's blood-making stem cells are not required to do anything much beyond their usual function. Human neural stem cells, when put into embryonic mice, have shown to migrate through the mouse's brain and add insulation to the neurons that lack it.

In the light of new knowledge, stem cell biologists are making more guarded predictions about the proximity of SCT. So much remains to be understood that it is hard to tell the aspect of their biology that may hold therapeutic promise. Regeneration and SCT are promising aspects of regenerative medicine but both are still at the research stage.

It would be a mistake to oversell it and promise too much, too early.