Periodic Reporting for period 4 - IniReg (Mechanisms of Regeneration Initiation)
Période du rapport: 2021-10-01 au 2022-03-31
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 key mechanisms of regeneration initiation. We use 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.
In this project, we identified and mechanistically dissected how these animals rapidly induce an efficient regeneration program in response to tissue loss. Starting our analyses in planarians, we identified the MAPK/ERK signaling pathway as one of the key switches in the decision whether this program is started or not. In a next step, we could show that this switch is conserved among vertebrates using zebrafish and spiny mice as model organisms. Strikingly, by manipulating this switch, we could turn the scarring response of mice that normally do not regenerate, into a pro-regenerative wound response, enabling tissue growth and hair follicle neogenesis.
To follow up on the results obtained in this project, we will focus our studies on essential mammalian organs, such as the skin and the heart. We expect that our findings may eventually be useful for the development of regenerative therapies after severe skin damage and heart attack.
In this project, we identified and mechanistically dissected how these animals rapidly induce an efficient regeneration program in response to tissue loss. Starting our analyses in planarians, we identified the MAPK/ERK signaling pathway as one of the key switches in the decision whether this program is started or not. In a next step, we could show that this switch is conserved among vertebrates using zebrafish and spiny mice as model organisms. Strikingly, by manipulating this switch, we could turn the scarring response of mice that normally do not regenerate, into a pro-regenerative wound response, enabling tissue growth and hair follicle neogenesis.
To follow up on the results obtained in this project, we will focus our studies on essential mammalian organs, such as the skin and the heart. We expect that our findings may eventually be useful for the development of regenerative therapies after severe skin damage and heart attack.
IniReg was aimed at a) characterizing wound response programs in terms of different levels of gene expression and cell behaviour, 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.
First, we analyzed the early response to injury on transcriptional, translational and cellular level. Using planarians and zebrafish, we identified the MAPK/ERK pathway as a key player in the distinction 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 (Owlarn et al., 2017, Nat Commun).
To transfer our findings to an animal model closer to humans, we have established one of the first spiny mouse colonies in Europe. Spiny mice are the only mammals known to be capable of regenerating large portions of their back skin, as well as ear punches. We analyzed gene expression programs and candidate regulators of regeneration in the spiny mouse and identified genes and pathways that lead to efficient regeneration of the skin. For instance, we could show that the MAPK/ERK pathway is at the crossroad between regeneration and scarring and can be manipulated to promote regenerative processes in the skin (Tomasso et al., 2022, pre-print on bioRxiv). We also developed an injury model for the heart and demonstrate that spiny mice repair their heart more efficiently than their non-regenerating relatives, probably due to specific properties of the cardiac scar (Koopmans et al., 2021, NPJ Regen Med). Exploring the underlying mechanisms of improved heart repair in the spiny mouse may provide alternatives to the current cardiomyocyte-centric treatment approaches in the future.
First, we analyzed the early response to injury on transcriptional, translational and cellular level. Using planarians and zebrafish, we identified the MAPK/ERK pathway as a key player in the distinction 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 (Owlarn et al., 2017, Nat Commun).
To transfer our findings to an animal model closer to humans, we have established one of the first spiny mouse colonies in Europe. Spiny mice are the only mammals known to be capable of regenerating large portions of their back skin, as well as ear punches. We analyzed gene expression programs and candidate regulators of regeneration in the spiny mouse and identified genes and pathways that lead to efficient regeneration of the skin. For instance, we could show that the MAPK/ERK pathway is at the crossroad between regeneration and scarring and can be manipulated to promote regenerative processes in the skin (Tomasso et al., 2022, pre-print on bioRxiv). We also developed an injury model for the heart and demonstrate that spiny mice repair their heart more efficiently than their non-regenerating relatives, probably due to specific properties of the cardiac scar (Koopmans et al., 2021, NPJ Regen Med). Exploring the underlying mechanisms of improved heart repair in the spiny mouse may provide alternatives to the current cardiomyocyte-centric treatment approaches in the future.
In the course of the project, we have successfully established a new mammalian model for investigating regeneration initiation – the spiny mouse. Initial experiments in planarians and zebrafish, in the first part of the project, uncovered a conserved role of MAPK/ERK signaling in regeneration initiation. We transferred these findings to spiny mouse regeneration paradigms, and could manifest this pathway as a major hub in the mammalian regeneration process. Our results place this pathway at the crossroad between regeneration and scarring, as its manipulation can favour one process over the other. Based on these findings and comparative gene expression datasets from spiny mice and their non-regenerative relatives, such as house mice and gerbils, we will now continue to characterize the molecular events that occur after injury in spiny mice to filter out those processes that may provide new avenues to regenerative therapies. We will also make our datasets available for the research community as part of a public searchable database.