Harnessing the regenerative potential of interleukin11 to enhance heart repair
Abstract Balancing between regenerative processes and fibrosis is crucial for heart repair, yet strategies regulating this balance remain a barrier to developing therapies. The role of Interleukin 11 (IL11) in heart regeneration remains controversial, as both regenerative and fibrotic functions have...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54060-0 |
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| author | Kwangdeok Shin Anjelica Rodriguez-Parks Chanul Kim Isabella M. Silaban Yu Xia Jisheng Sun Chenyang Dong Sunduz Keles Jinhu Wang Jingli Cao Junsu Kang |
| author_facet | Kwangdeok Shin Anjelica Rodriguez-Parks Chanul Kim Isabella M. Silaban Yu Xia Jisheng Sun Chenyang Dong Sunduz Keles Jinhu Wang Jingli Cao Junsu Kang |
| author_sort | Kwangdeok Shin |
| collection | DOAJ |
| description | Abstract Balancing between regenerative processes and fibrosis is crucial for heart repair, yet strategies regulating this balance remain a barrier to developing therapies. The role of Interleukin 11 (IL11) in heart regeneration remains controversial, as both regenerative and fibrotic functions have been reported. 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. Notably, il11a induction in uninjured hearts also activates the quiescent epicardium to produce epicardial progenitor cells, which later differentiate into cardiac fibroblasts. Consequently, prolonged il11a induction indirectly leads to persistent fibroblast emergence, resulting in cardiac 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. |
| format | Article |
| id | doaj-art-8a897809690b47ca90ddb1a6586c68f0 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-8a897809690b47ca90ddb1a6586c68f02024-11-10T12:31:54ZengNature PortfolioNature Communications2041-17232024-11-0115111310.1038/s41467-024-54060-0Harnessing the regenerative potential of interleukin11 to enhance heart repairKwangdeok Shin0Anjelica Rodriguez-Parks1Chanul Kim2Isabella M. Silaban3Yu Xia4Jisheng Sun5Chenyang Dong6Sunduz Keles7Jinhu Wang8Jingli Cao9Junsu Kang10Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin - MadisonDepartment of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin - MadisonDepartment of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin - MadisonDepartment of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin - MadisonCardiovascular Research Institute, Department of Cell and Developmental Biology, Weill Cornell Medical CollegeCardiology Division, School of Medicine, Emory UniversityDepartments of Statistics and of Biostatistics and Medical Informatics, University of Wisconsin - MadisonDepartments of Statistics and of Biostatistics and Medical Informatics, University of Wisconsin - MadisonCardiology Division, School of Medicine, Emory UniversityCardiovascular Research Institute, Department of Cell and Developmental Biology, Weill Cornell Medical CollegeDepartment of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin - MadisonAbstract Balancing between regenerative processes and fibrosis is crucial for heart repair, yet strategies regulating this balance remain a barrier to developing therapies. The role of Interleukin 11 (IL11) in heart regeneration remains controversial, as both regenerative and fibrotic functions have been reported. 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. Notably, il11a induction in uninjured hearts also activates the quiescent epicardium to produce epicardial progenitor cells, which later differentiate into cardiac fibroblasts. Consequently, prolonged il11a induction indirectly leads to persistent fibroblast emergence, resulting in cardiac 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.https://doi.org/10.1038/s41467-024-54060-0 |
| spellingShingle | Kwangdeok Shin Anjelica Rodriguez-Parks Chanul Kim Isabella M. Silaban Yu Xia Jisheng Sun Chenyang Dong Sunduz Keles Jinhu Wang Jingli Cao Junsu Kang Harnessing the regenerative potential of interleukin11 to enhance heart repair Nature Communications |
| title | Harnessing the regenerative potential of interleukin11 to enhance heart repair |
| title_full | Harnessing the regenerative potential of interleukin11 to enhance heart repair |
| title_fullStr | Harnessing the regenerative potential of interleukin11 to enhance heart repair |
| title_full_unstemmed | Harnessing the regenerative potential of interleukin11 to enhance heart repair |
| title_short | Harnessing the regenerative potential of interleukin11 to enhance heart repair |
| title_sort | harnessing the regenerative potential of interleukin11 to enhance heart repair |
| url | https://doi.org/10.1038/s41467-024-54060-0 |
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