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Education: Regeneration

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Regeneration versus Reparation

Regeneration is an organism’s ability to fully restore lost or damaged tissues' form and function.

Unfortunately the ability of human tissue to regenerate is limited.  For example, one of our biggest organs, the skin, does not regenerate but instead it scars. Scars are our skin's way of keeping a record of injury.

Not every skin injury results in scarring. If this were the case, every time we scratch our skin to sooth an itch, it would scar – after a few years we would be completely covered with scars and we would not survive. Instead, superficial scratches injure or destroy only the skin cells on the surface, which are quickly replaced by healthy cells, enabling our skin to return to its normal form and function, i.e. regeneration. We know that in skin the depth of an injury makes the difference between scarring and regeneration. If the injury is deeper than a given depth, the so-called basal membrane,  (a thin layer between the most superficial skin layer, Epidermis and the deeper, Dermis), a scar will form, if not, the damaged tissue will regenerate.

Why did we “forget” how to regenerate?

The amount or depth of injury is not the only variable that determines if tissues regenerate or not. Age is also an important factor. In the case of skin, we know that the younger we are, the smaller the scars on our skin will be after an injury.  If we consider very young humans, fetuses still in their mother’s womb, instead of scarring their skin regenerates after injury! We know this because of recent advances in surgery that now make it possible to operate on fetuses, in utero, to repair certain congenital malformations.  In these surgeries, even deep incisions in the skin (deeper than the basal membrane) heal without scaring. Based on this observation we use the term “scarless” and “fetal” wound healing interchangeably.

We now know that there are special proteins, build by cells, that act as modulators of DNA-transcription, that regulate both scarring and regeneration. In skin, for example, Tgf-β, a protein, which has 3 different forms, plays an important role in both processes. High concentrations of Tgfβ-3 are present in fetal “scarless” wound healing whereas in adult wounds “with scars” high levels of Tgfβ-1 and -2 are present. This has been demonstrated in adult wounds, in which case inhibiting Tgfβ-1 and -2 or adding Tgfβ-3 reduces scar formation.

What other animals can regenerate their body parts?

Looking around the animal kingdom, there are many species that can regenerate almost 100% of their body parts, like Planaria (flat worms) or Hydra´s.

Planaria, regenerating
(Sources: [1], [2])

Other animals that are closer to humans also regenerate. These include Salamanders and Urodels that like worms can regenerate their heart, jaws, major parts of the brain, and entire limbs. Rather than scaring the stump of an amputated salamander limb forms a clump of stem cells called a blastema (red circle in figure), which in a period of about 2-3 months, grows all the different cell types and tissues needed to rebuild an entirely new and fully functioning limb. Amazingly, if you re-amputate this newly regrown limb it will simply regrow again, as many times as you amputate it!

Salamander, regenerating limb
(Sources: [1], [2])

Even closer to humans, some mammals also regenerate body parts. Each season male deer loose and regenerate an entire pair of antlers.

Deer, regenerate their antlers every year
(Sources: [1], [2])

Besides superficial skin what else can regenerate in humans?

In humans several different tissues regenerate. For example, our nails our hair and our skin are constantly regenerating, the inner lining of the uterus regenerates monthly during a woman’s reproductive years, and our liver. If up to 2/3s of our liver is removed or destroyed by disease, it will regenerate and restore full function. In this latter example, while it’s normal size and function are restored, the liver does not truly regenerate, because the cells in the "regenerated" liver are not the same as those in the healthy liver. Just the same, many tissues in our body do know how to regenerate. The fact that as adults, some of our tissues regenerate and the fact that as fetuses most of our tissues regenerate suggests that the ability to regenerate is programmed in our genes.

Can we regenerate lost limbs?

In spite of the regenerative capabilities mentioned above adult mammals (humans, rats, mice) do not regenerate more complex structures like lost limbs. When we loose a limb, due to injury, the remaining stump heals with a scar and does not regenerate.  If this happens, and we’re lucky, and quick, if we retrieve the amputated limb and bring it to a hospital where there are specially trained surgeons, they can reattach it. In these cases, if the surgery is successful, and you are young, you can expect your reattached limb to regain almost complete function.

It is thought that if a human embryo, in the first 3 months of life, looses its limb it will regenerate, though we know of no evidence to support this claim. It has, however been well documented that young children, below the age of 10, regenerate amputated fingertips.

Human, regenerating fingertip

This ability to regenerate is lost with age. However, as in the case of limb reattachment, the younger the patient the better the return of form and function. For optimal regeneration of the fingertip in children it is important that the wound left after amputation not be surgically closed with sutures but left open to heal on its own. While this treatment may sound strange, it works! If left open the wound of a child’s amputated fingertip will regenerate into a new fingertip.

Initially the regeneration of a child’s fingertip may not sound like a big deal, but this is further evidence we have the information of how to regenerate programmed in our genes, we just need to figure out how to turn it back on in adults!

How can we turn limb regeneration back on in adults?

All the the above-cited examples of regeneration in animals added to the fact that human fetuses grow new limbs suggests that we possess the information “programed in our genes” to re-grow or regenerate these tissues as adults.  In adults this “regenerative program” is turned off or overwhelmed by other programs. It is with this in mind that we research "development" i.e. how our limbs and our face grow in the first place, when we are fetuses. We hope that with this knowledge we should be able to restored or “turn back on” this ability to grow hands and faces in adults.

Has there ever been reported blastema-formation in human?

A long accepted rule has been that mammals do not grow blastemas. However, forty years ago an orthopedic surgeon by the name of Robert Becker, having observed that small electrical currents accelerated bone growth, applied electrical stimulation (ES) to the stump of an amputated rat limb. He claimed that by doing this he was able to induce blastemas to grow in rats, just like the ones seen in salamanders. Although he was not able to get the entire limb to regrow, the partial regeneration he reported was a great step and his experiments dominated the scientific literature and the lay press for some time. Other researchers later independently reproduced Becker’s findings but this approach has remained largely silent in the literature, until now. In our laboratory we are in the process of reproducing the experiments Becker and the other scientists performed.

Other sources of regeneration research

Basic regeneration and Axolotl limb regeneration:


Becker´s work and electromagnetism: