Role of Il-11 signaling in adult heart and fin regeneration in zebrafish

In adult mammals, tissue damage after myocardial infarction induces myofibroblast differentiation and the formation of a permanent, functionally inert scar. However, the molecular mechanisms that govern myofibroblast differentiation and scarring remain poorly understood. Some vertebrates like zebrafish display a remarkable regenerative potential with only limited and transient fibrosis after tissue damage, including in the heart. Here, employing comparative expression profiling coupled with loss-of-function approaches, we identified the canonical Interleukin-11/Stat3 signaling axis as a core component of regeneration in zebrafish. Notably, animals with loss of Interleukin-11 receptor (Il11ra) function reach adulthood without overt developmental defects, but exhibit strongly impaired cardiac regeneration with increased myofibroblast differentiation and the formation of a permanent collagenous scar, similar to what is observed in adult mammals. Using zebrafish fate-mapping approaches, reporter lines and human primary cell culture methods, we provide evidence that Interleukin-11 signaling limits endothelial-to-myofibroblast transdifferentiation and maintains a pro-regenerative niche to promote cardiac regeneration. Altogether, our data reveal a vital role for endothelial Interleukin-11/Stat3 signaling in containing injury-induced cardiac fibrosis. 96 hours post cryoinjury cardiac ventricle samples from adult il11ra mutant vs. wild-type were analyzed in duplicates with each replicate derived by pooling 2 ventricles. 24 hours post amputation caudal fin samples from adult il11ra mutant vs. wild-type were analyzed in triplicates with each replicate derived from single fins.