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Mechanisms of Regeneration Initiation

Periodic Reporting for period 2 - IniReg (Mechanisms of Regeneration Initiation)

Reporting period: 2018-10-01 to 2020-03-31

Injury poses a key threat to all multicellular organisms. However, while some animals can fully restore lost body structures, others can only prevent further damage by mere wound healing. Which molecular mechanisms determine whether regeneration is induced or not is an unsettled fundamental question. IniReg aims at identifying the key mechanisms of regeneration initiation. We are using different naturally regenerating model organisms, such as the planarian flatworm S. mediterranea, the zebrafish D. rerio, and the African spiny mouse A. cahirinus, all of which have extraordinary regenerative abilities compared to some of their close relatives. In this project, we have been characterizing and mechanistically dissecting how these animals rapidly induce an efficient regeneration program in response to tissue loss and define the key switches that determine whether a wound regenerates. Combining the astonishing regenerative abilities of these animals with new technologies, we are comprehensively describing the molecular changes and their dynamics occurring during the amputation response. Next, we are functionally characterizing the regeneration-initiating signals and their target pathways combining loss-/gain-of-of function approaches and phenotypic assays. IniReg will not only uncover conserved mechanisms of regeneration initiation but will also identify the switches that must be levered to induce regeneration in non-regenerating organisms, such as humans. As we focus our studies on essential organs, such as the skin and the heart, we expect that our findings can be used in the future to improve the clinical outcomes after severe skin damage and heart attack.
IniReg aims at a) characterizing the wound response in planarians and regenerating vertebrate model organisms in terms of different levels of gene expression, b) identifying and characterizing the molecular key players that distinguish regenerating from non-regenerating wounds, c) identifying those key players that are suitable to manipulate regeneration outcomes for improving regeneration in poor regenerators.

During the first reporting period, we have developed a ribosome profiling protocol for planarians and analysed the early response to injury on both translational and transcriptional level. Using planarians and zebrafish, we identified the MAPK/ERK pathway as a key player in the distinction simple wound healing vs. regeneration of the missing tissues and could answer a long-standing problem in the regeneration field: also wounds that do not regenerate and only heal, express regeneration initiation signals - yet, they are incapable of interpreting them as such. This study was published in Nature Communications.
To transfer our findings to an animal model closer to humans, we have established one of the first African spiny mouse colonies in Europe. African spiny mice are the only mammals known to be capable of regenerating large portions of their back skin, as well as ear punches and potentially other organs. A mammalian model of natural regeneration, such as the African spiny mouse, will reveal those mechanisms and key players that may be most relevant for improving regeneration also in humans.
In the second half of the funding period, IniReg will build on the datasets generated during the first period and continue to nail down and characterize the key players that may be used to manipulate wounds to adopt a more favourable healing outcome in non-regenerating organisms. The final aim is to transfer this knowledge to concrete mammalian tissue contexts, such as the damaged skin and infarcted heart, in order to identify a molecular toolset for promoting regeneration of these organs in humans in the future.