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- 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.

Origin and function of activated fibroblast states during zebrafish heart regeneration

“…1a), which we read out later in the adult heart (all lineage trees are shown in Supplementary Figs. [14][15][16][17]. By sequencing scars and transcriptomes from the same single cells, we could build lineage trees that revealed the shared developmental origins of the cell types (Fig.…”

“…Many pathways and factors involved in heart regeneration have been described [7][8][9][10][11] . Important molecular signals for zebrafish heart regeneration emanate from the epicardium and endocardium 3,[11][12][13][14] . Other cell types are required for regeneration: inflammation is an early response to cryoinjury, and depletion of macrophages leads to delayed regeneration 15,16 .…”

IL-6 coaxes cellular dedifferentiation as a pro-regenerative intermediate that contributes to pericardial ADSC-induced cardiac repair

“…In the present experiments, we found that tissue content of IL-6/STAT3 signaling was an exquisite inducer of cardiomyocyte into a dedifferential status, likely acting in a same way as another IL-6 family members, OSM and IL-11 in mammalian heart [ 11 ] and zebrafish [ 10 ], suggesting that IL-6 family/STAT3 signaling is a conservative pathway to initiate dedifferential step under malignant stress [ 49 ]. The dedifferentiated cardiomyocytes exhibited a typical morphological alternation characterized by sarcomeric disorganization, relocation cardiac proteins towards the cell wall (marginalization), reduced cell–cell junctions and virtually increased cell mitosis markers (Aurora B and pH3 in Fig.…”

“…Induction of cardiac dedifferential process involves multiple regulatory molecules, including microRNA, transcriptional factors, and paracrine cytokines [ 9 ]. Interleukin-6 (IL-6) family members are known to be important regulators that orchestrate dedifferential process during heart regeneration [ 10 ]. Oncostatin M (OSM) has been reported to be a master regulator of cardiomyocyte dedifferentiation in adult mammalian heart [ 11 ], and recently also to play a role in neonatal heart regeneration [ 12 ].…”

“…Cytokines of IL-6 family utilize the common IL-6 signal transducer, gp130, either homodimerization or heterodimerization, to stimulate multiple pathways including JAK/STAT (Janus kinase/signal transducers and activators of transcription), ERK (extracellular-signal-regulated kinase) and PKB (protein kinase B) [ 13 ]. Notably, in zebrafish after apical resection, a dynamic induction of IL-6 family-mediated Jak1/STAT3 signaling accompanied by cytokine production has been found in the regenerative progress [ 10 ], and inhibition of STAT3 in cardiomyocytes restrict the injury-induced proliferation and regeneration, indicating IL-6/STAT3 cascade is functionally important to cardiomyocyte regeneration, preferentially in the context of injury [ 14 ]. Moreover, the role of IL-6/STAT3 cascade in adult mammalian is also implicitly exemplified in a self-limited model of myocarditis in which compensatory proliferation of pre-existing cardiomyocytes was triggered by robust activation of STAT3 activity [ 15 ].…”