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.
