Vitamin C facilitates direct cardiac reprogramming by inhibiting reactive oxygen species
Abstract Background After myocardial infarction, the lost myocardium is replaced by fibrotic tissue, eventually progressively leading to myocardial dysfunction. Direct reprogramming of fibroblasts into cardiomyocytes via the forced overexpression of cardiac transcription factors Gata4, Mef2c, and Tb...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Stem Cell Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13287-023-03615-x |
| _version_ | 1797350095897755648 |
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| author | Juntao Fang Qiangbing Yang Renée G. C. Maas Michele Buono Bram Meijlink Dyonne Lotgerink Bruinenberg Ernest Diez Benavente Michal Mokry Alain van Mil Li Qian Marie-José Goumans Raymond Schiffelers Zhiyong Lei Joost P. G. Sluijter |
| author_facet | Juntao Fang Qiangbing Yang Renée G. C. Maas Michele Buono Bram Meijlink Dyonne Lotgerink Bruinenberg Ernest Diez Benavente Michal Mokry Alain van Mil Li Qian Marie-José Goumans Raymond Schiffelers Zhiyong Lei Joost P. G. Sluijter |
| author_sort | Juntao Fang |
| collection | DOAJ |
| description | Abstract Background After myocardial infarction, the lost myocardium is replaced by fibrotic tissue, eventually progressively leading to myocardial dysfunction. Direct reprogramming of fibroblasts into cardiomyocytes via the forced overexpression of cardiac transcription factors Gata4, Mef2c, and Tbx5 (GMT) offers a promising strategy for cardiac repair. The limited reprogramming efficiency of this approach, however, remains a significant challenge. Methods We screened seven factors capable of improving direct cardiac reprogramming of both mice and human fibroblasts by evaluating small molecules known to be involved in cardiomyocyte differentiation or promoting human-induced pluripotent stem cell reprogramming. Results We found that vitamin C (VitC) significantly increased cardiac reprogramming efficiency when added to GMT-overexpressing fibroblasts from human and mice in 2D and 3D model. We observed a significant increase in reactive oxygen species (ROS) generation in human and mice fibroblasts upon Doxy induction, and ROS generation was subsequently reduced upon VitC treatment, associated with increased reprogramming efficiency. However, upon treatment with dehydroascorbic acid, a structural analog of VitC but lacking antioxidant properties, no difference in reprogramming efficiency was observed, suggesting that the effect of VitC in enhancing cardiac reprogramming is partly dependent of its antioxidant properties. Conclusions Our findings demonstrate that VitC supplementation significantly enhances the efficiency of cardiac reprogramming, partially by suppressing ROS production in the presence of GMT. Graphical abstract |
| first_indexed | 2024-03-08T12:39:53Z |
| format | Article |
| id | doaj.art-e3965e3745d94f5a8c07effa85a5711d |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-03-08T12:39:53Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj.art-e3965e3745d94f5a8c07effa85a5711d2024-01-21T12:12:56ZengBMCStem Cell Research & Therapy1757-65122024-01-0115111610.1186/s13287-023-03615-xVitamin C facilitates direct cardiac reprogramming by inhibiting reactive oxygen speciesJuntao Fang0Qiangbing Yang1Renée G. C. Maas2Michele Buono3Bram Meijlink4Dyonne Lotgerink Bruinenberg5Ernest Diez Benavente6Michal Mokry7Alain van Mil8Li Qian9Marie-José Goumans10Raymond Schiffelers11Zhiyong Lei12Joost P. G. Sluijter13Experimental Cardiology laboratory, Department of Cardiology, University Medical Center UtrechtExperimental Cardiology laboratory, Department of Cardiology, University Medical Center UtrechtExperimental Cardiology laboratory, Department of Cardiology, University Medical Center UtrechtExperimental Cardiology laboratory, Department of Cardiology, University Medical Center UtrechtExperimental Cardiology laboratory, Department of Cardiology, University Medical Center UtrechtExperimental Cardiology laboratory, Department of Cardiology, University Medical Center UtrechtExperimental Cardiology laboratory, Department of Cardiology, University Medical Center UtrechtExperimental Cardiology laboratory, Department of Cardiology, University Medical Center UtrechtExperimental Cardiology laboratory, Department of Cardiology, University Medical Center UtrechtMcAllister Heart Institute, University of North CarolinaDepartment of Cell and Chemical Biology, Leiden University Medical CentreCDL Research, University Medical Center UtrechtExperimental Cardiology laboratory, Department of Cardiology, University Medical Center UtrechtExperimental Cardiology laboratory, Department of Cardiology, University Medical Center UtrechtAbstract Background After myocardial infarction, the lost myocardium is replaced by fibrotic tissue, eventually progressively leading to myocardial dysfunction. Direct reprogramming of fibroblasts into cardiomyocytes via the forced overexpression of cardiac transcription factors Gata4, Mef2c, and Tbx5 (GMT) offers a promising strategy for cardiac repair. The limited reprogramming efficiency of this approach, however, remains a significant challenge. Methods We screened seven factors capable of improving direct cardiac reprogramming of both mice and human fibroblasts by evaluating small molecules known to be involved in cardiomyocyte differentiation or promoting human-induced pluripotent stem cell reprogramming. Results We found that vitamin C (VitC) significantly increased cardiac reprogramming efficiency when added to GMT-overexpressing fibroblasts from human and mice in 2D and 3D model. We observed a significant increase in reactive oxygen species (ROS) generation in human and mice fibroblasts upon Doxy induction, and ROS generation was subsequently reduced upon VitC treatment, associated with increased reprogramming efficiency. However, upon treatment with dehydroascorbic acid, a structural analog of VitC but lacking antioxidant properties, no difference in reprogramming efficiency was observed, suggesting that the effect of VitC in enhancing cardiac reprogramming is partly dependent of its antioxidant properties. Conclusions Our findings demonstrate that VitC supplementation significantly enhances the efficiency of cardiac reprogramming, partially by suppressing ROS production in the presence of GMT. Graphical abstracthttps://doi.org/10.1186/s13287-023-03615-xVitamin CCardiac reprogrammingROSCardiac regeneration |
| spellingShingle | Juntao Fang Qiangbing Yang Renée G. C. Maas Michele Buono Bram Meijlink Dyonne Lotgerink Bruinenberg Ernest Diez Benavente Michal Mokry Alain van Mil Li Qian Marie-José Goumans Raymond Schiffelers Zhiyong Lei Joost P. G. Sluijter Vitamin C facilitates direct cardiac reprogramming by inhibiting reactive oxygen species Stem Cell Research & Therapy Vitamin C Cardiac reprogramming ROS Cardiac regeneration |
| title | Vitamin C facilitates direct cardiac reprogramming by inhibiting reactive oxygen species |
| title_full | Vitamin C facilitates direct cardiac reprogramming by inhibiting reactive oxygen species |
| title_fullStr | Vitamin C facilitates direct cardiac reprogramming by inhibiting reactive oxygen species |
| title_full_unstemmed | Vitamin C facilitates direct cardiac reprogramming by inhibiting reactive oxygen species |
| title_short | Vitamin C facilitates direct cardiac reprogramming by inhibiting reactive oxygen species |
| title_sort | vitamin c facilitates direct cardiac reprogramming by inhibiting reactive oxygen species |
| topic | Vitamin C Cardiac reprogramming ROS Cardiac regeneration |
| url | https://doi.org/10.1186/s13287-023-03615-x |
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