The genetics of tissue regeneration
Many human diseases and cancers result in damage to healthy tissue which is not replaced. Similarly, traumatic injury can also lead to a loss of functional tissue, in addition to the production of excessive scarring that further impairs quality of life. However, in contrast to humans, many organisms demonstrate significant regenerative abilities following tissue damage or injury, usually without scar formation. For example, urodele amphibians (newts and salamanders) can regenerate the entire complex structure of a limb following amputation, while zebrafish have been studied extensively for their ability to completely regenerate damaged cardiac tissue following induced myocardial infarction (heart attack). Thus, while the equivalent human tissues fail to repair themselves, many of these same tissues in other organisms can readily regenerate, suggesting the process may be inducible in tissues that are normally incapable of regrowth. Our research aims to characterize the fundamental genetic factors and mechanisms that underlie a tissues ability to regenerate, with a view to improving regenerative ability.
In many organisms, tissues frequently lose regenerative capacity as they mature from juvenile to adult stages. This phenomenon provides an ideal opportunity to investigate regeneration, as a single tissue can be examined at times of high and low regenerative capacity, and the differences responsible for successful regrowth can be identified. However, many of the organisms that lose regenerative capacity in this way are unsuitable for laboratory study.
Therefore, in order to study regeneration, we are using the well established and exceptionally powerful genetic model organism Drosophila melanogaster, the common fruit fly. The larval organs of Drosophila, known as imaginal discs, are able to regenerate following various types of damage. However, this ability is limited to early larval life, and is progressively lost as the larvae mature.
The wing imaginal disc, which forms the adult wing structures, is a non-essential organ that has been extensively studied as a model for tissue growth and development. The strong conservation of genetic pathways and the similarities in regenerative processes between Drosophila and mammals will ensure these findings will have relevance to human tissue regeneration.
Our previous research revealed the existence of a mechanism that controls the expression of genes involved in regeneration. We characterized a damage-activated region of the genome that, when activated by injury, leads to the expression of two nearby genes, WNT1 (wg) and WNT6. This Damage-Responsive and Maturity-Silenced (DRMS) enhancer induces expression of these genes only upon damage in younger tissues. As the tissue matures, the enhancer region becomes inactivated by epigenetic silencing, thus limiting damage-induced gene expression and contributing to the loss of regenerative capacity of this tissue. Importantly, this mechanism still permits developmental enhancers to shape expression of both genes in undamaged tissues, demonstrating how the regulation of a regeneration program can be separated from developmental gene expression.
We have found that this mechanism is potenitally widespread, controlling the expression of many other genes required for regeneration. Our work aims to characterize this mechanism, identify the target genes that might be regulated by it and are therefore involved in the regeneration program, and ultimately to elucidate genetic manipulations that can be used to augment regenerative ability.
In a new direction for our research, we are also interested in understanding how tissues respond to different types of cell death, specifically contrasting the regenerative response to necrosis versus apoptosis. Update to come soon!