Key result
Induction of il11a in the zebrafish heart initiates robust cardiomyocyte proliferation, and combining it with an ERK inhibitor mitigates il11a-induced fibrosis to enhance heart repair.
Why the study?
Balancing regenerative processes and fibrosis is crucial for heart repair, but the contribution of Interleukin11 to heart regeneration was poorly understood.
Combinatorial treatment of il11a induction with ERK inhibition enhances cardiomyocyte proliferation while mitigating fibrosis in zebrafish hearts, offering a potential therapeutic avenue for cardiac repair.
Balancing between regenerative processes and fibrosis is crucial for heart repair, yet strategies regulating this balance remain a barrier to developing therapies. While Interleukin11 (IL11) is known as a fibrotic factor, its contribution to heart regeneration is poorly understood. We uncovered that il11a, an Il11 homolog in zebrafish, can trigger robust regenerative programs in zebrafish hearts, including cardiomyocytes proliferation and coronary expansion, even in the absence of injury. However, prolonged il11a induction in uninjured hearts causes persistent fibroblast emergence, resulting in fibrosis. While deciphering the regenerative and fibrotic effects of il11a , we found that il11 -dependent fibrosis, but not regeneration, is mediated through ERK activity, suggesting to potentially uncouple il11a dual effects on regeneration and fibrosis. To harness the il11a ’s regenerative ability, we devised a combinatorial treatment through il11a induction with ERK inhibition. This approach enhances cardiomyocyte proliferation with mitigated fibrosis, achieving a balance between regenerative processes and fibrosis. Thus, we unveil the mechanistic insights into regenerative il11 roles, offering therapeutic avenues to foster cardiac repair without exacerbating fibrosis.
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Shin et al. (2024) studied Cardiac injury and heart regeneration. il11a overexpression (with or without ERK inhibitor U0126) vs. Control (uninduced or vehicle) was evaluated on Cardiomyocyte proliferation at 14 days post-injury. Induction of il11a in the zebrafish heart initiates robust cardiomyocyte proliferation, and combining it with an ERK inhibitor mitigates il11a-induced fibrosis to enhance heart repair.
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