Harnessing the regenerative potential ofinterleukin11to enhance heart repair

Abstract

Balancing between regenerative processes and fibrosis is crucial for heart repair1. 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 heart2–4, its contribution to heart regeneration remains poorly understood. Here, we uncovered thatil11acan 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 prolongedil11ainduction in uninjured hearts causes persistent fibroblast emergence, resulting in cardiac fibrosis. While deciphering the regenerative and fibrotic effects, we found thatil11-dependent fibrosis, but notil11-dependent regeneration, is mediated through ERK activity, implying that the dual effects ofil11aon regeneration and fibrosis can be uncoupled. To harness the regenerative ability ofil11afor injured hearts, we devised a combinatorial treatment throughil11ainduction 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 ofil11signaling, offering the potential therapeutic avenues that utilizes a paracrine regenerative factor to foster cardiac repair without exacerbating the fibrotic responses.