The Future Potential of Human Limb Regeneration

Amy Patel

Limb regeneration in humans seems like such a foreign concept, yet invertebrates such as starfish, worms, sponges, and hydra have the ability to regenerate missing tails, legs, and some species even a head.  As far as vertebrates go, the most common type of animal studied for regeneration is the amphibian. Salamanders and newts can regenerate missing legs, tails and eyes in just weeks!  Why can’t mammals possess the same super powers of regeneration as these smaller animals?

Generating a single type of tissue from basic cells is now a commonly studied and well understood concept for humans.  Sitting in a lab and feeding growth factors to cells in the proper environment can relatively easily yield epithelium, gastric tissue, cartilage, or even bone. The problem with limbs is that they contain various tissues arranged perfectly to form a fully functioning body part that carries out daily activities with ease. Even a seemingly simple fingertip contains a nail, epidermal tissue, blood vessels, adipose tissue, nerves, and a unique fingerprint. The goal of human limb regeneration is to significantly reduce the need for prosthetic limbs and completely eliminate the need for limb amputation, this would be an amazing step towards the future of regenerative medicine.

How limb regeneration works

In order for regeneration to occur in a complex body part (such as a limb with multiple tissue types), pluripotent stem cells are required to be able to generate several mature types of tissue that will organise into an anatomically correct body part. Many studies have been conducted with salamanders to understand the sequence of developmental events leading to limb and tail regeneration.

Upon removal of part of a limb, the salamander grows an epidermal stump to cover and protect the injured area.  However, under the stump is where the real magic occurs in a developing blastema of undifferentiated, multipotent cells. Stem cells from the animal’s spinal cord migrate to the blastema and develop into the various cell types needed, which include muscle, cartilage, mesoderm, and neural cells. The initial formation of muscle and cartilage begin to form an elongating limb stump, once those form a somewhat strong structure to protect the internal immature limb, neurons will grow within the clump to eventually form a fully functional limb.

In flatworm studies, we have discovered that regeneration of the tail can occur, which may also be simultaneous with head regeneration!  Flatworm regeneration occurs differently than in the more complex species previously mentioned, the salamander.  Flatworms naturally possess totipotent stem cells that exist in their body throughout a lifetime and upon removal of a flatworm’s head and/or tail, this reserve of cells is called into action. Hedgehog signaling factors dictate the totipotent stem cells to form a head rather than a tail and vis-versa; therefore enough of the animal’s body must be left to participate in cell-cell communication between what exists and what will be regenerated.  RNA interference is responsible for regeneration of the correct part in the correct location.

These are just two examples of how different species have their own way to regenerate desired tissues.  Humans follow their own path via limited partially differentiated cells in the liver, skin, and digestive system providing the very basic function of replacing only damaged or dead cells.  Unfortunately, natural limb regeneration does not fit within our scope of everyday tissue damage.

The path to human limb regeneration

The fingertip has been the initial experimental factor of human limb regeneration for years.  It’s a great starting point since it has all the same tissues as a full limb, however if a human experiment doesn’t pan out, the subject can still live & function without a fingertip. In 2005, the value of porcine intestinal tissue was publicised thanks to Lee Spievack. He accidently cut-off an entire inch of one of his fingers and was persuaded to try tissue regeneration via Dr. Stephen Badylak’s collagen powder derived from the bladder of a pig.  After approximately one month of daily application of this powder to his missing fingertip, Spievack’s fingertip grew back consistently with all the naturally occurring tissues and soon gained full function.

This worked because the powder acted as an acellular matrix with high amounts of collagen and protein to allow the body’s natural cells to form around this strong scaffold. Dr. Badylak had accidently created SIS, small intestinal submucosa, in 1987 at Purdue University when his team was in search of a vascular graft.  When they extracted a porcine bladder, removed all the cells, dried out the remaining matrix, and grinded it into a fine powder, little did they know that they had created a masterpiece.  Although no one has reported complete limb regeneration yet, there have been several U.S. military uses of SIS to help soldiers heal from battle-related injuries including thigh muscle regrowth, deep wound healing, and multi-layer epidermal burn repair.


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Image 1 via Science Photo Library
Image 2 via Stem Tech Labs
Image 3 via Purdue University

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