Harnessing the regenerative potential ofinterleukin11to enhance heart repair

Abstract

ABSTRACTBalancing 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 thatil11a, an Il11homolog in zebrafish, can trigger robust regenerative programs in zebrafish hearts, including cardiomyocytes proliferation and coronary expansion, even in the absence of injury. However, prolongedil11ainduction in uninjured hearts causes persistent fibroblast emergence, resulting in fibrosis. While deciphering the regenerative and fibrotic effects ofil11a, we found thatil11-dependent fibrosis, but not regeneration, is mediated through ERK activity, suggesting to potentially uncoupleil11adual effects on regeneration and fibrosis. To harness theil11a’s regenerative ability, we devised a combinatorial treatment throughil11ainduction 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 regenerativeil11roles, offering therapeutic avenues to foster cardiac repair without exacerbating fibrosis.