Interleukin-11 signaling promotes cellular reprogramming and limits fibrotic scarring during tissue regeneration

Abstract

Damage-induced fibrotic scarring limits tissue regeneration in mammals and is a leading cause of morbidity. In contrast, species like zebrafish can regenerate damaged tissues without excessive fibrosis. However, whether specific signaling pathways can both limit fibrosis and promote regeneration is unclear. Here, we show that interleukin-11 (Il-11)/Stat3 signaling has such a dual function. Zebrafish lacking Il-11 receptor function display severely compromised heart, fin, and scale regeneration. Deep phenotyping and transcriptional analysis of adult hearts and fins show that Il-11 signaling drives cellular reprogramming to orchestrate global and tissue-specific regenerative programs and broadly antagonizes hallmarks of adult mammalian scarring. Mechanistically, our data indicate that IL-11 signaling in endothelial cells antagonizes profibrotic transforming growth factor–β signaling and endothelial-to-mesenchymal transition, limiting scarring and promoting cardiomyocyte repopulation, after injury. Overall, our findings position damage-induced Il-11/Stat3 signaling in a key role limiting fibrosis and promoting regeneration, revealing novel targets for regenerative therapies. dedifferentiation, proliferation, and migration, allowing regeneration (13–17). Although scar formation clearly correlates negatively with regeneration, the existence of specific upstream mechanisms that both promote cellular reprogramming and limit scarring is unclear. In this study, through genetic loss-of-function approaches, lineage tracing, the examination of regeneration in various tissues and developmental stages, and combinatorial transcriptome profiling, we show that interleukin-11 (Il-11)/signal transducer and activator of transcription 3 (Stat3) signaling plays two roles: (i) It promotes cellular reprogramming by orchestrating regenerative programs, and (ii) it limits injury-induced mammalian-like scarring.