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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.

SUBMITTER: Allanki S

PROVIDER: S-EPMC8442930 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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

Allanki Srinivas S Strilic Boris B Scheinberger Lilly L Onderwater Yeszamin L YL Marks Alora A Günther Stefan S Preussner Jens J Kikhi Khrievono K Looso Mario M Stainier Didier Y R DYR Reischauer Sven S

Science advances 20210908 37

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. ...[more]

PMID: 34516874

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Project description:BackgroundIn the context of spinal cord injury (SCI), infiltrating macrophages assume prominence as the primary inflammatory cells within the lesion core, where the fibrotic scar is predominantly orchestrated by platelet-derived growth factor receptor beta (PDGFRβ+) fibroblasts. Galectin-3, a carbohydrate-binding protein of the lectin family, is notably expressed by infiltrating hematogenous macrophages and mediates cell-cell interactions. Although Galectin-3 has been shown to contribute to the endocytic internalization of PDGFRβ in vitro, its specific role in driving fibrotic scar formation after SCI has not been determined.MethodsWe employed a crush mid-thoracic (T10) SCI mouse model. Galectin-3 inhibition after SCI was achieved through intrathecal injection of the Galectin-3 inhibitor TD139 or in situ injection of lentivirus carrying Galectin-3-shRNA (Lv-shLgals3). A fibrosis-induced mice model was established by in situ injection of platelet-derived growth factor D (PDGFD) or recombinant Galectin-3 (rGalectin-3) into the uninjured spinal cord. Galectin-3 internalization experiments were conducted in PDGFRβ+ fibroblasts cocultured in conditioned medium in vitro.ResultsWe identified the spatial and temporal correlation between macrophage-derived Galectin-3 and PDGFRβ in fibroblasts from 3 to 56 days post-injury (dpi). Administration of TD139 via intrathecal injection or in situ injection of Lv-shLgals3 effectively mitigated fibrotic scar formation and extracellular matrix deposition within the injured spinal cord, leading to better neurological outcomes and function recovery after SCI. Furthermore, the fibrosis-inducing effects of exogenous PDGFD in the uninjured spinal cord could be blocked by TD139. In vitro experiments further demonstrated the ability of PDGFRβ+ fibroblasts to internalize Galectin-3, with Galectin-3 inhibition resulting in reduced PDGFRβ expression.ConclusionsOur finding underscores the pivotal role of macrophage-derived Galectin-3 in modulating the sustained internalized activation of PDGFRβ within fibroblasts, providing a novel mechanistic insight into fibrotic scarring post-SCI.

Dataset Information

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

Publications

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

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