Repairing the Damage

Although some species of amphibians – such as salamanders and newts – are able to regenerate lost or damaged tissue, the capacity for regeneration diminished as vertebrates evolved and adult mammals generally have limited regenerative capacity. Over a decade ago, it was discovered that the Murphy Roths Large (MRL) mouse strain was able to regenerate new epidermis, new hair follicles, and new cartilage to repair punch holes in the ears, unlike other strains of mice that close the holes with scar tissue. The MRL mice were later shown to have the ability to repair damaged heart muscle and spinal cord with restoration of normal structure and function and to have some limited capacity for digit re-growth. Scientists have been trying to identify the gene or genes that are responsible for the increased capacity for regeneration in MRL mice and researchers at the Wistar Institute and Washington University have now shown that the p21 gene is involved in regulating the regeneration process.

The team showed that p21, a cell cycle regulator, was found to be consistently inactive in cells from MRL mice. When they looked at p21 knockout mice, they found that, unlike normal mice which heal wounds by forming a scar, mice that lack p21 begin by forming a blastema, a mass of cells capable of rapid growth and de-differentiation which behave more like embryonic stem cells than adult mammalian cells. The p21 knockout mice were able to replace missing or damaged tissue with healthy tissue that showed no signs of scarring.

Since the cyclin-dependent kinase p21 is one of the best characterized downstream targets of the tumour suppressor p53, knockout of p21 might be expected to increase the incidence of cancer and other studies have suggested that p21-deficient mice develop tumours at an earlier age than their wild-type counterparts and are more susceptible to the effects of some carcinogens. Although increased DNA damage was observed in the present study, there was also an increased incidence of apoptosis and no net increase in the incidence of cancer. If MRL mice and p21 knockout mice are a good model for tissue regeneration in humans, temporary inactivation of the p21 gene could eventually be used to speed up wound healing in people.

The study is published in PNAS.