Harnessing the regenerative potential of interleukin11 to enhance heart repair.

Balancing between regenerative processes and fibrosis is crucial for heart repair 1 . However, strategies to regulate the balance between these two process are a barrier to the development of effective therapies for heart regeneration. While Interleukin 11 (IL11) is known as a fibrotic factor for the heart 2-4 , its contribution to heart regeneration remains poorly understood. Here, we uncovered that il11a can initiate robust regenerative programs in the zebrafish heart, including cell cycle reentry of cardiomyocytes (CMs) and coronary expansion, even in the absence of injury. However, the prolonged il11a induction in uninjured hearts causes persistent fibroblast emergence, resulting in cardiac fibrosis. While deciphering the regenerative and fibrotic effects, we found that il11 -dependent fibrosis, but not il11 -dependent regeneration, is mediated through ERK activity, implying that the dual effects of il11a on regeneration and fibrosis can be uncoupled. To harness the regenerative ability of il11a for injured hearts, we devised a combinatorial treatment through il11a induction with ERK inhibition. Using this approach, we observed enhanced CM proliferation with mitigated fibrosis, achieving a balance between stimulating regenerative processes and curbing fibrotic outcomes. Thus, our findings unveil the mechanistic insights into regenerative roles of il11 signaling, offering the potential therapeutic avenues that utilizes a paracrine regenerative factor to foster cardiac repair without exacerbating the fibrotic responses.