Matured hiPSC-derived cardiomyocytes possess dematuration plasticity
Human induced Pluripotent Stem Cell-derived cardiomyocytes (hiPSC-CMs) are increasingly used to identify potential factors capable of inducing endogenous cardiomyocyte proliferation to regenerate the injured heart. L-type calcium channel blockers have previously been identified as a class of factors...
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Elsevier
2025-06-01
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| Series: | Journal of Molecular and Cellular Cardiology Plus |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2772976125000145 |
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| author | Fang Meng Maxwell Kwok Yen Chin Hui Ruofan Wei Alejandro Hidalgo-Gonzalez Anna Walentinsson Henrik Andersson Frederik Adam Bjerre Qing-Dong Wang Ditte C. Andersen Ellen Ngar-Yun Poon Daniela Später David C. Zebrowski |
| author_facet | Fang Meng Maxwell Kwok Yen Chin Hui Ruofan Wei Alejandro Hidalgo-Gonzalez Anna Walentinsson Henrik Andersson Frederik Adam Bjerre Qing-Dong Wang Ditte C. Andersen Ellen Ngar-Yun Poon Daniela Später David C. Zebrowski |
| author_sort | Fang Meng |
| collection | DOAJ |
| description | Human induced Pluripotent Stem Cell-derived cardiomyocytes (hiPSC-CMs) are increasingly used to identify potential factors capable of inducing endogenous cardiomyocyte proliferation to regenerate the injured heart. L-type calcium channel blockers have previously been identified as a class of factors capable of inducing matured hiPSC-CMs to proliferate. However, the mechanism by which L-type calcium channel blockers promote hiPSC-CM proliferation remains unclear. Here we provide evidence that matured hiPSC-CMs possess plasticity to undergo dematuration in response to certain pharmacological compounds. Consistent with primary cardiomyocyte maturation during perinatal development, we found that centrosome disassembly occurs in hiPSC-CMs during plate-based, temporal, maturation. A small molecule screen identified nitrendipine, an L-type calcium channel blocker, and 1-NA-PP1, a Src kinase inhibitor, as factors capable of inducing centrosome reassembly in a subpopulation of hiPSC-CMs. Furthermore, centrosome-positive hiPSC-CMs were more likely to exhibit cell cycle activity than centrosome-negative hiPSC-CMs. In contrast, neither nitrendipine or 1-NA-PP1 induced centrosome reassembly, or cell cycle activity, in neonatal rat ventricular myocytes (NRVMs). Differential bulk transcriptome analysis indicated that matured hiPSC-CMs, but not NRVMs, treated with nitrendipine or 1-NA-PP1 undergo dematuration. ScRNA transcriptome analysis supported that matured hiPSC-CMs treated with either nitrendipine or 1-NA-PP1 undergo dematuration. Collectively, our results indicate that matured hiPSC-CMs, but not primary NRVMs, possess plasticity to undergo dematuration in response to certain pharmacological compounds such as L-type calcium channel blockers and Src-kinase inhibitors. This study shows that once mature, hiPSC-CMs may not maintain their maturity under experimental conditions which may have implications for experimental systems where the state of hiPSC-CM maturation is relevant. |
| format | Article |
| id | doaj-art-cbccdb5bf21c4fc6b362e36396047a63 |
| institution | OA Journals |
| issn | 2772-9761 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Molecular and Cellular Cardiology Plus |
| spelling | doaj-art-cbccdb5bf21c4fc6b362e36396047a632025-08-20T02:06:20ZengElsevierJournal of Molecular and Cellular Cardiology Plus2772-97612025-06-011210029510.1016/j.jmccpl.2025.100295Matured hiPSC-derived cardiomyocytes possess dematuration plasticityFang Meng0Maxwell Kwok1Yen Chin Hui2Ruofan Wei3Alejandro Hidalgo-Gonzalez4Anna Walentinsson5Henrik Andersson6Frederik Adam Bjerre7Qing-Dong Wang8Ditte C. Andersen9Ellen Ngar-Yun Poon10Daniela Später11David C. Zebrowski12Department of Biology, New York University, New York, NY, USA; Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, The People's Republic of China; Hong Kong Hub of Paediatric Excellence (HK HOPE), The Chinese University of Hong Kong, Hong Kong Children's Hospital, Hong Kong SAR, The People's Republic of ChinaDepartment of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, The People's Republic of China; Hong Kong Hub of Paediatric Excellence (HK HOPE), The Chinese University of Hong Kong, Hong Kong Children's Hospital, Hong Kong SAR, The People's Republic of China; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, The People's Republic of ChinaDepartment of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, The People's Republic of China; Hong Kong Hub of Paediatric Excellence (HK HOPE), The Chinese University of Hong Kong, Hong Kong Children's Hospital, Hong Kong SAR, The People's Republic of ChinaDepartment of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, The People's Republic of China; Hong Kong Hub of Paediatric Excellence (HK HOPE), The Chinese University of Hong Kong, Hong Kong Children's Hospital, Hong Kong SAR, The People's Republic of ChinaIntegrated Cardio Metabolic Center (ICMC), Karolinska Institutet, Huddinge, Sweden; Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Murdoch Children's Research Institute (MCRI), Flemington, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, AustraliaTranslational Science & Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, SwedenBioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, SwedenAndersen Group, Department of Clinical Biochemistry, Odense University Hospital, Odense, Denmark; Clinical Institute, University of Southern Denmark, Odense, DenmarkBioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, SwedenAndersen Group, Department of Clinical Biochemistry, Odense University Hospital, Odense, Denmark; Clinical Institute, University of Southern Denmark, Odense, DenmarkDepartment of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, The People's Republic of China; Hong Kong Hub of Paediatric Excellence (HK HOPE), The Chinese University of Hong Kong, Hong Kong Children's Hospital, Hong Kong SAR, The People's Republic of China; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, The People's Republic of ChinaIntegrated Cardio Metabolic Center (ICMC), Karolinska Institutet, Huddinge, Sweden; Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Corresponding authors.Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, The People's Republic of China; Hong Kong Hub of Paediatric Excellence (HK HOPE), The Chinese University of Hong Kong, Hong Kong Children's Hospital, Hong Kong SAR, The People's Republic of China; Integrated Cardio Metabolic Center (ICMC), Karolinska Institutet, Huddinge, Sweden; Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; GenKardia Inc., USA; Corresponding authors.Human induced Pluripotent Stem Cell-derived cardiomyocytes (hiPSC-CMs) are increasingly used to identify potential factors capable of inducing endogenous cardiomyocyte proliferation to regenerate the injured heart. L-type calcium channel blockers have previously been identified as a class of factors capable of inducing matured hiPSC-CMs to proliferate. However, the mechanism by which L-type calcium channel blockers promote hiPSC-CM proliferation remains unclear. Here we provide evidence that matured hiPSC-CMs possess plasticity to undergo dematuration in response to certain pharmacological compounds. Consistent with primary cardiomyocyte maturation during perinatal development, we found that centrosome disassembly occurs in hiPSC-CMs during plate-based, temporal, maturation. A small molecule screen identified nitrendipine, an L-type calcium channel blocker, and 1-NA-PP1, a Src kinase inhibitor, as factors capable of inducing centrosome reassembly in a subpopulation of hiPSC-CMs. Furthermore, centrosome-positive hiPSC-CMs were more likely to exhibit cell cycle activity than centrosome-negative hiPSC-CMs. In contrast, neither nitrendipine or 1-NA-PP1 induced centrosome reassembly, or cell cycle activity, in neonatal rat ventricular myocytes (NRVMs). Differential bulk transcriptome analysis indicated that matured hiPSC-CMs, but not NRVMs, treated with nitrendipine or 1-NA-PP1 undergo dematuration. ScRNA transcriptome analysis supported that matured hiPSC-CMs treated with either nitrendipine or 1-NA-PP1 undergo dematuration. Collectively, our results indicate that matured hiPSC-CMs, but not primary NRVMs, possess plasticity to undergo dematuration in response to certain pharmacological compounds such as L-type calcium channel blockers and Src-kinase inhibitors. This study shows that once mature, hiPSC-CMs may not maintain their maturity under experimental conditions which may have implications for experimental systems where the state of hiPSC-CM maturation is relevant.http://www.sciencedirect.com/science/article/pii/S2772976125000145CardiomyocyteStem cellhiPSCProliferationDifferentiationMaturation |
| spellingShingle | Fang Meng Maxwell Kwok Yen Chin Hui Ruofan Wei Alejandro Hidalgo-Gonzalez Anna Walentinsson Henrik Andersson Frederik Adam Bjerre Qing-Dong Wang Ditte C. Andersen Ellen Ngar-Yun Poon Daniela Später David C. Zebrowski Matured hiPSC-derived cardiomyocytes possess dematuration plasticity Journal of Molecular and Cellular Cardiology Plus Cardiomyocyte Stem cell hiPSC Proliferation Differentiation Maturation |
| title | Matured hiPSC-derived cardiomyocytes possess dematuration plasticity |
| title_full | Matured hiPSC-derived cardiomyocytes possess dematuration plasticity |
| title_fullStr | Matured hiPSC-derived cardiomyocytes possess dematuration plasticity |
| title_full_unstemmed | Matured hiPSC-derived cardiomyocytes possess dematuration plasticity |
| title_short | Matured hiPSC-derived cardiomyocytes possess dematuration plasticity |
| title_sort | matured hipsc derived cardiomyocytes possess dematuration plasticity |
| topic | Cardiomyocyte Stem cell hiPSC Proliferation Differentiation Maturation |
| url | http://www.sciencedirect.com/science/article/pii/S2772976125000145 |
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