Vitamin C facilitates direct cardiac reprogramming by inhibiting reactive oxygen species

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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: [Figure not available: see fulltext.].

Original languageEnglish
Article number19
Pages (from-to)19
JournalStem Cell Research & Therapy [E]
Volume15
Issue number1
DOIs
Publication statusPublished - 17 Jan 2024

Keywords

  • Cardiac regeneration
  • Cardiac reprogramming
  • ROS
  • Vitamin C

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