Can People Regenerate Body Parts? (V of V)

Now, as we watch a salamander grow back an arm, we are no longer quite as mystified by how it happens. Soon humans might be able to harness this truly awesome ability ourselves, replacing damaged and diseased body parts at will, perhaps indefinitely.

Studies of deep wounds have shown that at least two populations of fibroblasts invade an injury during healing. Some of these cells are fibroblasts that reside in the dermis, and the others are derived from circulating fibroblastlike stem cells. Both types are attracted to the wound by signals from immune cells that have also rushed to the scene. Once in the wound, the fibroblasts migrate and proliferate, eventually producing and modifying the extracellular matrix of the area.

This early process is not that dissimilar to the regeneration response in a salamander wound, but the mammalian fibroblasts produce an excessive amount of matrix that becomes abnormally cross-linked as the scar tissue matures. In contrast, salamander fibroblasts stop producing matrix once the normal architecture has been restored. An exception to this pattern in mammals does exist, however. Wounds in fetal skin heal without forming scars—yielding perfect skin regeneration and indicating that the switch to a fibrotic response arises with the developmental maturation of the skin.

Although this difference could reflect a change in the biology of the fibroblasts, it is more likely a result of altered signaling from the extracellular wound environment modulating the behavior of the fibroblasts, which in turn suggests that therapeutically modifying those signals could change the healing response. At the same time, the fact that limb amputations during fetal stages of development do not result in regeneration of the limb reminds us that scar-free wound healing is likely to be necessary but not sufficient for regeneration.

To advance our understanding of what it will take to induce limb regeneration in people, we are continuing our work with mice. Our research group has already described a natural blastema in a mouse amputation injury, and our goal within the next year is to induce a blastema where it would not normally occur. Like the accessory-limb experiments in salamanders, this achievement would establish the minimal requirements for blastema formation. We hope that this line of investigation will also reveal whether, as we suspect, the blastema itself provides critical signaling that prevents fibrosis in the wound site.

If we succeed in generating a blastema in a mammal, the next big hurdle for us would be coaxing the site of a digit amputation to regenerate the entire digit. The complexity of that task is many times greater than regenerating a simple digit tip because a whole digit includes joints, which are among the most complicated skeletal structures formed in the body during embryonic development. Developmental biologists are still trying to understand how joints are made naturally, so building a regenerated mouse digit, joints and all, would be a major milestone in the regeneration field.

We hope to reach it in the next few years, and after that, the prospect of regenerating an entire mouse paw, and then an arm, will not seem so remote. Indeed, when we consider all that we have learned about wound healing and regeneration from studies in various animal models, the surprising conclusion is that we may be only a decade or two away from a day when we can regenerate human body parts. The striking contrast between the behavior of fibroblasts in directing the regeneration response in salamanders versus the fibrotic response leading to scarring in mammals suggests that the road to successful regeneration is lined with these cells.

Equally encouraging is the recent discovery by Howard Y. Chang and John L. Rinn of Stanford University that adult human fibroblasts, like salamander fibroblasts, retain a memory of the spatial coordinate system used to establish the body plan early in the embryo’s development. Given that such positional information is re­-quired for regeneration in salamanders, its existence in human fibroblasts enhances the feasibility of tapping into and activating developmental programs necessary for regeneration.

Now, as we watch a salamander grow back an arm, we are no longer quite as mystified by how it happens. Soon humans might be able to harness this truly awesome ability ourselves, replacing damaged and diseased body parts at will, perhaps indefinitely.

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Can People Regenerate Body Parts? (II of V)

Scientific American Magazine - By Ken Muneoka, Manjong Han and David M. Gardiner

Many years ago studies in the laboratory of our colleague Susan V. Bryant at the University of California, Irvine, demonstrated that the cells in the blastema are equivalent to the cells in the developing limb bud of the salamander embryo.

This discovery suggested that the construction of a limb by the blastema is essentially a recapitulation of the limb formation that took place during the animal’s original development. An important implication of this insight was that the same genetic program is involved in both situations, and because humans make limbs as embryos, in principle we should already have the necessary programming to regenerate them as adults, too. It seemed, therefore, that all scientists needed to do was figure out how to induce an amputated limb to form a blastema.

One of us (Gardiner)—working with Tetsuya Endo of U.C. Irvine a few years ago—took a minimalist approach to answering the basic question of how to make a blastema. Instead of studying amputation sites on the salamander, where a blastema would naturally form, we looked at simple wounds on the side of a salamander limb, which would normally heal just by regenerating the skin. Our idea was that such wounds are similar to the site of an amputated mammalian limb that fails to generate a new limb. If we could get an entire limb to grow where a simple wound-healing response would typically occur, then we could further dissect the regeneration process.

After we made a small incision in the salamander leg, epidermal cells migrated to cover and seal the wound, as they would at an amputation site, and fibroblasts from the dermis layer of the skin also moved in to replace the missing skin. But if we carefully deviated a nerve to the wound site, we could induce those fibroblasts to form a blastema instead. Marcus Singer of Case Western Reserve University had already demonstrated more than half a century ago that innervation was required for a regeneration response, but our experiments clarified that unknown factors provided by the nerve were influencing regeneration by altering the behavior of resident fibroblasts. These induced blastemas never progressed to the later stages of regeneration to form a new limb, however. One more ingredient was needed.

The key to inducing a blastema that produced a new limb was to graft a piece of skin from the opposite side of the limb to the wound site, which allowed fibroblasts from opposite regions of the limb to participate in the healing response. The resulting accessory limb was, of course, growing out at an abnormal location, but it was anatomically normal. So the basic recipe for making a blastema seemed relatively simple: you need a wound epidermis, nerves and fibroblasts from opposite sides of the limb.

With this minimal view of limb regeneration in mind, we began to focus on understanding the roles of the individual ingredients.

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