Targeting miRNA‐1a and miRNA‐15b: A Novel Combinatorial Strategy to Drive Adult Cardiac Regeneration
Abstract Despite its promise, cardiac regenerative therapy remains clinically elusive due to the difficulty of spatio‐temporal control of proliferative induction, and the need to coordinately reprogram multiple regulatory pathways to overcome the strict post‐mitotic state of human adult cardiomyocyt...
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Wiley
2025-06-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202414455 |
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| author | Ting Yuan Meiqian Wu Chaonan Zhu Hao Yu Minh Duc Pham Katharina Bottermann Yijie Mao Yue Wang Mathias Langner Mirko Peitzsch Arka Provo Das Silke Kauferstein Jonathan Ward Peter Mirtschink Andreas Michael Zeiher Stefanie Dimmeler Jaya Krishnan |
| author_facet | Ting Yuan Meiqian Wu Chaonan Zhu Hao Yu Minh Duc Pham Katharina Bottermann Yijie Mao Yue Wang Mathias Langner Mirko Peitzsch Arka Provo Das Silke Kauferstein Jonathan Ward Peter Mirtschink Andreas Michael Zeiher Stefanie Dimmeler Jaya Krishnan |
| author_sort | Ting Yuan |
| collection | DOAJ |
| description | Abstract Despite its promise, cardiac regenerative therapy remains clinically elusive due to the difficulty of spatio‐temporal control of proliferative induction, and the need to coordinately reprogram multiple regulatory pathways to overcome the strict post‐mitotic state of human adult cardiomyocytes. To address this unmet therapeutic need, a combinatorial miRNA interference screen is performed specifically targeting cardiac‐predominant miRNAs regulating key aspects of cardiomyocyte mitotic induction to cell‐cycle completion in neonatal rat cardiomyocytes. In doing so combinatorial interference of miRNA‐1a and miRNA‐15b (LNA‐1a/15b) is identified as drivers of adult cardiomyocyte proliferation. Due to miRNA‐1a/15b function on multiple processes modulating adult cardiomyocyte mitosis, its inhibition augmented adult cardiomyocyte cell‐cycle completion and daughter cell formation, and improved contractility in 3D human cardiac organoids, and in a mouse model of ST‐segment elevation myocardial infarction. Due to the cardiac‐restricted pattern of miRNA‐1a/15b expression, this strategy provides a feasible means for specific cardiomyocyte proliferative induction with minimal risk of neoplasm formation and off‐target toxicity. The approach further highlights an underutilized therapeutic strategy for simultaneous co‐regulation of multiple disease pathways through combinatorial interference of miRNAs. |
| format | Article |
| id | doaj-art-cfb020eb9e794145a8062f6f5cf28cdd |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-cfb020eb9e794145a8062f6f5cf28cdd2025-08-20T03:24:39ZengWileyAdvanced Science2198-38442025-06-011221n/an/a10.1002/advs.202414455Targeting miRNA‐1a and miRNA‐15b: A Novel Combinatorial Strategy to Drive Adult Cardiac RegenerationTing Yuan0Meiqian Wu1Chaonan Zhu2Hao Yu3Minh Duc Pham4Katharina Bottermann5Yijie Mao6Yue Wang7Mathias Langner8Mirko Peitzsch9Arka Provo Das10Silke Kauferstein11Jonathan Ward12Peter Mirtschink13Andreas Michael Zeiher14Stefanie Dimmeler15Jaya Krishnan16Department of Medicine Cardiology, Goethe University Hospital 60590 Frankfurt GermanyDepartment of Medicine Cardiology, Goethe University Hospital 60590 Frankfurt GermanyDepartment of Medicine Cardiology, Goethe University Hospital 60590 Frankfurt GermanyJilin Provincial Key Laboratory of Livestock and Poultry Feed and Feeding in the Northeastern Frigid Area College of Animal Sciences Jilin University Changchun 130062 ChinaInstitute for Cardiovascular Regeneration Centre for Molecular Medicine Goethe University Frankfurt am Main 60590 Frankfurt am Main GermanyInstitute for Pharmacology Medical Faculty and University Hospital Düsseldorf Heinrich‐Heine‐University Düsseldorf 40001 Düsseldorf GermanyDepartment of Medicine Cardiology, Goethe University Hospital 60590 Frankfurt GermanyDepartment of Medicine Cardiology, Goethe University Hospital 60590 Frankfurt GermanyInstitute for Clinical Chemistry and Laboratory Medicine University Hospital Dresden Fetscherstasse 74 01307 Dresden GermanyInstitute for Clinical Chemistry and Laboratory Medicine University Hospital Dresden Fetscherstasse 74 01307 Dresden GermanyDepartment of Medicine Cardiology, Goethe University Hospital 60590 Frankfurt GermanyDepartment of Legal Medicine University Hospital Frankfurt Goethe University 60590 Frankfurt am Main GermanyGenome Biologics Theodor‐Stern‐Kai 7 60590 Frankfurt am Main GermanyInstitute for Clinical Chemistry and Laboratory Medicine University Hospital Dresden Fetscherstasse 74 01307 Dresden GermanyInstitute for Cardiovascular Regeneration Centre for Molecular Medicine Goethe University Frankfurt am Main 60590 Frankfurt am Main GermanyInstitute for Cardiovascular Regeneration Centre for Molecular Medicine Goethe University Frankfurt am Main 60590 Frankfurt am Main GermanyDepartment of Medicine Cardiology, Goethe University Hospital 60590 Frankfurt GermanyAbstract Despite its promise, cardiac regenerative therapy remains clinically elusive due to the difficulty of spatio‐temporal control of proliferative induction, and the need to coordinately reprogram multiple regulatory pathways to overcome the strict post‐mitotic state of human adult cardiomyocytes. To address this unmet therapeutic need, a combinatorial miRNA interference screen is performed specifically targeting cardiac‐predominant miRNAs regulating key aspects of cardiomyocyte mitotic induction to cell‐cycle completion in neonatal rat cardiomyocytes. In doing so combinatorial interference of miRNA‐1a and miRNA‐15b (LNA‐1a/15b) is identified as drivers of adult cardiomyocyte proliferation. Due to miRNA‐1a/15b function on multiple processes modulating adult cardiomyocyte mitosis, its inhibition augmented adult cardiomyocyte cell‐cycle completion and daughter cell formation, and improved contractility in 3D human cardiac organoids, and in a mouse model of ST‐segment elevation myocardial infarction. Due to the cardiac‐restricted pattern of miRNA‐1a/15b expression, this strategy provides a feasible means for specific cardiomyocyte proliferative induction with minimal risk of neoplasm formation and off‐target toxicity. The approach further highlights an underutilized therapeutic strategy for simultaneous co‐regulation of multiple disease pathways through combinatorial interference of miRNAs.https://doi.org/10.1002/advs.202414455cardiac organoidscardiomyocyte proliferationmicroRNAsmyocardial infarction |
| spellingShingle | Ting Yuan Meiqian Wu Chaonan Zhu Hao Yu Minh Duc Pham Katharina Bottermann Yijie Mao Yue Wang Mathias Langner Mirko Peitzsch Arka Provo Das Silke Kauferstein Jonathan Ward Peter Mirtschink Andreas Michael Zeiher Stefanie Dimmeler Jaya Krishnan Targeting miRNA‐1a and miRNA‐15b: A Novel Combinatorial Strategy to Drive Adult Cardiac Regeneration Advanced Science cardiac organoids cardiomyocyte proliferation microRNAs myocardial infarction |
| title | Targeting miRNA‐1a and miRNA‐15b: A Novel Combinatorial Strategy to Drive Adult Cardiac Regeneration |
| title_full | Targeting miRNA‐1a and miRNA‐15b: A Novel Combinatorial Strategy to Drive Adult Cardiac Regeneration |
| title_fullStr | Targeting miRNA‐1a and miRNA‐15b: A Novel Combinatorial Strategy to Drive Adult Cardiac Regeneration |
| title_full_unstemmed | Targeting miRNA‐1a and miRNA‐15b: A Novel Combinatorial Strategy to Drive Adult Cardiac Regeneration |
| title_short | Targeting miRNA‐1a and miRNA‐15b: A Novel Combinatorial Strategy to Drive Adult Cardiac Regeneration |
| title_sort | targeting mirna 1a and mirna 15b a novel combinatorial strategy to drive adult cardiac regeneration |
| topic | cardiac organoids cardiomyocyte proliferation microRNAs myocardial infarction |
| url | https://doi.org/10.1002/advs.202414455 |
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