Group Jamie Morrison

Humans have a relatively limited tissue regeneration repertoire. Many tissues/organs, when they become damaged, remain functionally hindered physiologically for the remainder of that person’s life. The consequence of this is amplified when organs like the heart become damaged and the functional hindrance can lead to death. The red-spotted newt on the other hand can functionally regenerate multiple tissues/organs without scarring following damage i.e. limbs, heart, brain, lens, retina, spinal cord. This amazing process is even more extraordinary due to the fact that these vertebrate newts can achieve these regenerative feats as an adult organism. However, to date, the mechanisms that lie behind how these amphibians can regenerate so efficiently are poorly characterized. Despite the obvious phenotypical differences, this amphibian model organism shares many of the common cellular and molecular traits found in mammals. Therefore, we use the newt as a model organism to help “bridge the gap” between basic research carried out in the newts and therapeutic strategies for human ailments once thought untreatable (Figure 1).

 

Micro RNAs and cardiac regeneration

Recently published research conducted within my group has shown for the first time that the three-chambered heart of the adult vertebrate newt also regenerates following resection damage (1). We have started to assess the role microRNAs have during cardiac regeneration using the model system we have developed. MicroRNAs are recently discovered, highly conserved single-stranded RNA molecules of about 21-23 nucleotides in length, which regulate gene expression. We have identified several microRNAs that are significantly regulated during newt heart regeneration and we are currently identifying mRNA targets for these microRNAs. The information provided from the differential analysis of microRNAs at various time-points during heart regeneration in the newt will pinpoint how these small RNAs are implicated during various phases of this amazing regenerative process. The discovery of specific microRNAs required for heart regeneration in the newt will only benefit the development of microRNA based therapeutical strategies aimed at preventing cardiac remodeling in human pathological conditions.

Cardiosphere cultures

In order to fully utilize the pre-mentioned heart regeneration model system, we would like to confirm any results found in vivo, using an in vitro model system for newt heart regeneration. We have shown for the first time that cardiospheres can be isolated from newts. (Figure 2). Cardiospheres can be described as a spherical mass of cardiac stem cells. The cardiospheres have the ability of giving rise to the three cell populations of the heart; cardiomyocytes, smooth muscle cells and endothelial cells. The use of cardiosphere cultures from various mammalian animal models has enhanced our awareness that cardiac specific progenitor/stem cells can be obtained endogenously from cultured cardiac tissue. To be able to study the contribution newt cardiospheres have in a morphological and functional regenerating heart model can only go to benefit our understanding of how progenitor/stem cells are involved in cardiac regeneration. In addition, the fact that we can also isolate cardiospheres from newts, in a similar manner to mammalian animal models, demonstrates further how compatible these two chordates are comparatively.

 

 

RNA editing and regeneration

Regeneration amongst Urodele amphibians requires cellular plasticity but very little is known about the molecular mechanisms behind what controls the re-specification of certain cells in the regeneration environment. A tantalizing reality would be that various forms of regeneration could be governed by a single post-transcriptional mechanism that can alter the global control of plasticity and proliferation. RNA editing can affect gene regulation in many different ways, leading to a multitude of downstream effects (see Marie Öhman’s research pages). To date, the role of RNA editing, and its ability to change phenotypic plasticity, has not been studied in a regeneration context. To address whether RNA editing has a role in reparative regeneration, we are using the heart, limb and neuronal regeneration models in the newt to assess whether enzymes that drive RNA editing are differentially regulated at a transcriptional and translational level. Using numerous regeneration models allows us to compare whether regeneration is regulated in a globally related fashion, even though the molecular and cellular mechanisms that lie behind these regeneration processes are different from one another.