In last month’s issue we provided specific examples of stem cell therapies under development and in clinical trials. The emergence of such therapies shows why there is a “gold rush” of research and venture capital into regenerative medicine territory, as we discussed in the April issue.

This month, we digest exemplary advances made over the past 18 months in an even more extraordinary potential form of regenerative medicine: Regeneration itself, as practiced by salamanders, zebra fish, and even human fetuses.

How the Salamander Regenerates

When they lose a limb, salamanders regenerate the bones, muscle, skin, blood vessels, and nerves of a new one practically indistinguishable from the lost one. The tissues are generated from a blastema, a mass of cells that forms at the site of the injury. Blastemas were thought to contain pluripotent stem cells (able to turn into almost any adult cell) but it was discovered last year that the stem cells are unipotent progenitor cells—they regenerate only cells of the tissue that they came from. So a muscle stem cell in the blastema creates muscle cells in the regenerated limb, a bone stem cell creates only bone cells, and so on.

The finding is significant because, since we humans also have progenitor cells that replace different kinds of tissue, getting our cells to regenerate like a salamander’s might be easier than was supposed, though it still begs the question: Why don’t they?

Molecular Understanding of Regeneration

Perhaps they do, though to a much lesser extent. A form of white blood cell called a macrophage responds to kidney tissue injury by producing a protein (Wnt7b) known to be important to the formation of kidney tissues during embryonic organ development. In a mouse study, the protein helped initiate tissue repair and regeneration in injured kidneys. The same molecular pathway may be applicable to tissue regeneration and repair in other organs.

Regeneration in Zebra Fish

As we delve deeper into the molecular mechanics of the cells, the answer to why humans don’t regenerate like a salamander or zebra fish will become clearer. Late last year, the cellular pathway that paves the way for limb regeneration in zebra fish was discovered. It works by switching on genes that are switched off during embryonic development. The discovery should help explain why certain animals can do it and we cannot. Certain genes have a hand in the regeneration of damaged fin, heart, retinal, and other tissues, suggesting that the regeneration process is guided by a common molecular mechanism involving not one but multiple genes working together.

Regeneration Genes

However, in March this year the Wistar Institute discovered that a single gene, p21, appears to control—by its absence or inactivity—regeneration in mammals. We reported in November 2005 on the Institute’s serendipitous discovery (in 1996) of mammalian regeneration in a strain of experimental mice. It turns out that what gave them the power to regenerate was their lack of the p21 gene.

The Wistar researchers hope that “one day we’ll be able to accelerate healing in humans by temporarily inactivating the p21 gene.”

Human Heart Cells Regenerate

In the meantime, we can tweak the limited regeneration capability we already have, to produce therapies. Early last year it was discovered in Sweden that heart muscle cells are constantly renewed throughout life, though the rate declines as we get older—from 1 percent of cells replaced per year at age 25 to 0.45 percent at age 75. Over a normal lifespan, fewer than 50 per cent of the heart’s muscle cells are replaced. Therefore, if we could stimulate the process of heart cell renewal, we might have a new way to treat heart disease and replace damaged heart muscle.

Protein Therapy to Regenerate Heart Muscle

And it turns out we probably can. At about the same time as the Swedish discovery, it was found that a protein called neuregulin1 added to a petri dish containing mature heart-muscle cells taken from mice helped the cells to divide and multiply. In a follow-up in-vivo test in mice with heart damage, 12 weeks of daily injections of the protein reduced the size of the enlarged hearts, which then worked “significantly better.”

As a promising therapy, neuregulin1 joins periostin and fibroblast growth factor, both of which were also found (in 2007 and 2006 respectively) to regenerate heart muscle cells, reduce scarring, and improve function.

Spinal Cord Regeneration Through Dissolving Scar Tissue

Speaking of scar-reduction: By digesting scar tissue that blocks re-growth of nerves in damaged spinal cords, an improved enzyme therapy could facilitate recovery in SCI patients. The improvement enables the enzyme (chrondroitinase ABC) to remain active for weeks without needing continuous injection through implanted catheters and pumps. Furthermore, the improved enzyme therapy can be used in combination with sustained delivery of neurotrophin-3 (a protein growth factor that helps to support the survival and differentiation of neurons). In animal tests, the combination led to significant improvement in locomotor function.

Regenerating Nerves

Although damaged or severed nerves can regenerate, they do so at only about one millimeter a day, and to get to the area (say, the hand) that has lost function, they need the original nerve sheath to guide them to it, and they need to get there within about three months, otherwise the hand loses the capacity to function ever again. At a millimeter a day, a nerve severed at the wrist might make it in time to save the hand, but a nerve severed at the shoulder would not.
The solution: Lab-grown nerves. They do not transmit signals themselves, but they do maintain the hand’s viability while the body’s own regenerating nerve, using the lab-grown nerve as a guide, creeps forward. The breakthrough in making the engineered nerves quickly grow long enough was achieved by stretching them—growing them under tension. The result was growth at a speed almost 100 times faster than normal.

In rats that had part of their leg nerves cut out, function was restored to the legs within four months, using the engineered nerves.

As of early this year, the longest nerve grown was approximately 10 centimeters. The stretching process has been shown to work with neurons taken from human organ donors, and a trial of the human-derived implants in patients with nerve injuries is anticipated in the next two years.

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There are still those who think that the Human Genome Project, which started most of this, has failed to deliver on its potential. We disagree.


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