One of the most encouraging signs that human limb regeneration is a feasible goal is the fact that our fingertips already have an intrinsic ability to regenerate.
This observation was made first in young children more than 30 years ago, but since then similar findings have been reported in teenagers and even adults. Fostering regeneration in a fingertip amputation injury is apparently as simple as cleaning the wound and covering it with a simple dressing. If allowed to heal naturally, the fingertip restores its contour, fingerprint and sensation and undergoes a varying degree of lengthening. The success of this conservative treatment of fingertip amputation injuries has been documented in medical journals thousands of times.
Interestingly, the alternative protocol for such injuries typically included operating to suture a skin flap over the amputation wound, a “treatment” that we now know will inhibit regeneration even in the salamander because it interferes with formation of the wound epidermis. The profound message in these reports is that human beings have inherent regenerative capabilities that, sadly, have been suppressed by some of our own traditional medical practices. It is not easy to study how natural human fingertip regeneration works because we cannot go around amputating fingers to do experiments, but the same response has been demonstrated in both juvenile and adult mice by several researchers.
In recent years two of us (Muneoka and Han) have been studying the mouse digit-tip regeneration response in more detail. We have determined that a wound epidermis does form after digit-tip amputation, but it covers the regenerating wound much more slowly than occurs in the salamander. We have also shown that during digit-tip regeneration, important embryonic genes are active in a population of undifferentiated, proliferating cells at the wound site, indicating that they are blastema cells. And indirect evidence suggests that they are derived from fibroblasts residing in the interstitial connective tissues and in bone marrow.
To explore the roles of specific genes and growth factors during the mouse-digit regeneration response, we developed a tissue culture that serves as a model for fetal mouse-digit regeneration. With it, we found that if we experimentally depleted a growth factor called bone morphogenetic protein 4 (BMP4) from the fetal amputation wound, we inhibited regeneration. In addition, we have shown that a mutant mouse lacking a gene called Msx1 is unable to regenerate its digit tips. In the fetal digit tip, Msx1 is critical to the production of BMP4, and we were able to restore the regeneration response by adding BMP4 to the wound in the Msx1-deficient mouse, confirming BMP4’s necessity for regeneration.
Studies by Cory Abate-Shen and her colleagues at the Robert Wood Johnson Medical School have also demonstrated that the protein encoded by Msx1 inhibits differentiation in a variety of cell types during embryonic development. That link to the control of differentiation suggests that the protein plays a role in the regeneration response by causing cells to dedifferentiate. Although Msx1 is not active during the early dedifferentiation stages of salamander limb regeneration, its sister gene Msx2 is one of the first genes reactivated during regeneration and very likely serves a similar function.
The idea of regenerating a human limb may still seem more like fantasy than a plausible possibility, but with insights such as those we have been describing, we can evaluate in a logical stepwise manner how it might happen. An amputated human limb results in a large and complex wound surface that transects a number of different tissues, including epidermis, dermis and interstitial connective tissue, adipose tissue, muscle, bone, nerve and vasculature. Looking at those different tissue types individually, we find that most of them are actually very capable of regenerating after a small-scale injury.
In fact, the one tissue type within a limb that lacks regenerative ability is the dermis, which is composed of a heterogeneous population of cells, many of which are fibroblasts—the same cells that play such a pivotal role in the salamander regeneration response. After an injury in humans and other mammals, these cells undergo a process called fibrosis that “heals” wounds by depositing an unorganized network of extracellular matrix material, which ultimately forms scar tissue.
The most striking difference between regeneration in the salamander and regenerative failure in mammals is that mammalian fibroblasts form scars and salamander fibroblasts do not. That fibrotic response in mammals not only hampers regeneration but can be a very serious medical problem unto itself, one that permanently and progressively harms the functioning of many organs, such as the liver and heart, in the aftermath of injury or disease. info@goliveideas4.com >> http://www.goliveideas4.com
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