Harnessing the regenerative potential of interleukin11 to enhance heart repair

• Type of Material: Article
• Authors: Kwangdeok Shin, University of Wisconsin; Anjelica Rodriguez-Parks, University of Wisconsin; Chanul Kim, University of Wisconsin; Isabella M. Silaban, University of Wisconsin; Yu Xia, Weill Cornell Medical College; Jisheng Sun, Emory University; Chenyang Dong, University of Wisconsin; Sunduz Keles, University of Wisconsin; Jinhu Wang, Emory University; Jingli Cao, Weill Cornell Medical College; Junsu Kang, University of Wisconsin
• Language: English
• Date: 2024-01-30
• Publisher: National Institutes of Health
• Publication Version: Preprint (Prior to Peer Review)
• Copyright Statement: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): https://www.biorxiv.org/content/10.1101/2024.01.29.577788v2
• Title of Journal or Parent Work: bioRxiv
• Grant/Funding Agency: University of Wisconsin; Stem Cell and Regenerative Medicine Center; National Institutes of Health
• Grant/Funding Information: University of Wisconsin Institute for Clinical and Translational Research (UW ICTR) pilot grant (JK); National Institutes of Health grant R01 HL 151522 (JK); National Institutes of Health, University of Wisconsin Carbone Cancer Center Support grant P30 CA 014520 (JK); National Institutes of Health grant R01 HL 155607 (JC); National Institutes of Health grant R01 HL 142762 (JW); Stem Cell and Regenerative Medicine Center Research Training Award (KS); National Institutes of Health grant R01 HL 166518 (JC); National Institutes of Health grant R35 GM 137878 (JK)
• Keywords: Interleukin11 (IL11); cardiomyocytes proliferation; coronary expansion; heart repair; ERK activity; fibroblast emergence; fibrosis; regeneration; zebrafish
• Research Categories: Medicine

Abstract

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.