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Positive feedback between retinoic acid and 2-phospho-L-ascorbic acid trisodium salt during somatic cell reprogramming

  • Zhang, Mengdan1, 2, 3, 4
  • Li, Qian1, 5
  • Yang, Tingting1, 2, 3, 4
  • Meng, Fei1, 2, 3, 4
  • Lai, Xiaowei1, 2, 3, 4
  • Liang, Lining1, 2, 3
  • Li, Changpeng1, 2, 3
  • Sun, Hao1, 2, 3, 4
  • Sun, Jiaqi2
  • Zheng, Hui1, 2, 3, 4, 6
  • 1 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Ave., Science City, Guangzhou, Huangpu District, 510530, China , Guangzhou (China)
  • 2 Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, 510700, China , Guangzhou (China)
  • 3 Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, 510530, China , Guangzhou (China)
  • 4 University of Chinese Academy of Sciences, Beijing, 100049, China , Beijing (China)
  • 5 Guangzhou Medical University, Guangzhou, 511436, China , Guangzhou (China)
  • 6 Institutes for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China , Beijing (China)
Published Article
Cell Regeneration
Springer Singapore
Publication Date
Oct 01, 2020
DOI: 10.1186/s13619-020-00057-1
Springer Nature


Retinoic acid (RA) and 2-phospho-L-ascorbic acid trisodium salt (AscPNa) promote the reprogramming of mouse embryonic fibroblasts to induced pluripotent stem cells. In the current studies, the lower abilities of RA and AscPNa to promote reprogramming in the presence of each other suggested that they may share downstream pathways at least partially. The hypothesis was further supported by the RNA-seq analysis which demonstrated a high-level overlap between RA-activated and AscPNa activated genes during reprogramming. In addition, RA upregulated Glut1/3, facilitated the membrane transportation of dehydroascorbic acid, the oxidized form of L-ascorbic acid, and subsequently maintained intracellular L-ascorbic acid at higher level and for longer time. On the other hand, AscPNa facilitated the mesenchymal-epithelial transition during reprogramming, downregulated key mesenchymal transcriptional factors like Zeb1 and Twist1, subsequently suppressed the expression of Cyp26a1/b1 which mediates the metabolism of RA, and sustained the intracellular level of RA. Furthermore, the different abilities of RA and AscPNa to induce mesenchymal-epithelial transition, pluripotency, and neuronal differentiation explain their complex contribution to reprogramming when used individually or in combination. Therefore, the current studies identified a positive feedback between RA and AscPNa, or possibility between vitamin A and C, and further explored their contributions to reprogramming.

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