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

MPS-Authors
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Allanki,  Srinivas
Developmental Genetics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224195

Strilic,  Boris
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons228718

Marks,  Alora
Developmental Genetics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224128

Guenther,  Stefan
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224386

Preussner,  Jens
Bioinformatics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons239396

Kikhi,  Khrievono
Developmental Genetics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224384

Looso,  Mario
Bioinformatics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224278

Stainier,  Didier Y. R.
Developmental Genetics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224272

Reischauer,  Sven
Developmental Genetics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Citation

Allanki, S., Strilic, B., Scheinberger, L., Onderwater, Y. L., Marks, A., Guenther, S., et al. (2021). Interleukin-11 signaling promotes cellular reprogramming and limits fibrotic scarring during tissue regeneration. SCIENCE ADVANCES, 7(37): eabg6497. doi:10.1126/sciadv.abg6497.


Cite as: http://hdl.handle.net/21.11116/0000-0009-431F-A
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-beta 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.