5-aza-2-deoxycytidine and valproic acid in combination with chir99021 and a83-01 induce pluripotency genes expression in human adult somatic cells

Alain Aguirre-Vázquez, Luis A. Salazar-Olivo, Xóchitl Flores-Ponce, Ana L. Arriaga-Guerrero, Dariela Garza-Rodríguez, María E. Camacho-Moll, Iván Velasco, Fabiola Castorena-Torres, Nidheesh Dadheech, Mario Bermúdez de León*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

A generation of induced pluripotent stem cells (iPSC) by ectopic expression of OCT4, SOX2, KLF4, and c-MYC has established promising opportunities for stem cell research, drug discovery, and disease modeling. While this forced genetic expression represents an advantage, there will always be an issue with genomic instability and transient pluripotency genes reactivation that might preclude their clinical application. During the reprogramming process, a somatic cell must undergo several epigenetic modifications to induce groups of genes capable of reactivating the endogenous pluripotency core. Here, looking to increase the reprograming efficiency in somatic cells, we evaluated the effect of epigenetic molecules 5-aza-2-deoxycytidine (5AZ) and valproic acid (VPA) and two small molecules reported as reprogramming enhancers, CHIR99021 and A83-01, on the expression of pluripotency genes and the methylation profile of the OCT4 promoter in a human dermal fibroblasts cell strain. The addition of this cocktail to culture medium increased the expression of OCT4, SOX2, and KLF4 expression by 2.1-fold, 8.5-fold, and 2-fold, respectively, with respect to controls; concomitantly, a reduction in methylated CpG sites in OCT4 promoter region was observed. The epigenetic cocktail also induced the expression of the metastasis-associated gene S100A4. However, the epigenetic cocktail did not induce the morphological changes characteristic of the reprogramming process. In summary, 5AZ, VPA, CHIR99021, and A83-01 induced the expression of OCT4 and SOX2, two critical genes for iPSC. Future studies will allow us to precise the mechanisms by which these compounds exert their reprogramming effects.

Original languageEnglish
Article number1909
Pages (from-to)1-12
Number of pages12
JournalMolecules
Volume26
Issue number7
DOIs
Publication statusPublished - 1 Apr 2021
Externally publishedYes

Bibliographical note

Funding Information:
Funding: This research was funded by Instituto Mexicano del Seguro Social, grant number FIS/IMSS/ PROT/PRIO/16/058 and Consejo Nacional de Ciencia y Tecnología-México, grant number 272815. A.A.V. was supporting by Consejo Nacional de Ciencia y Tecnología and Instituto Mexicano del Seguro Social (Scholarships No. 588906 and 97205589, respectively).

Funding Information:
This research was funded by Instituto Mexicano del Seguro Social, grant number FIS/IMSS/ PROT/PRIO/16/058 and Consejo Nacional de Ciencia y Tecnolog?a-M?xico, grant number 272815. A.A.V. was supporting by Consejo Nacional de Ciencia y Tecnolog?a and Instituto Mexicano del Seguro Social (Scholarships No. 588906 and 97205589, respectively).

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

All Science Journal Classification (ASJC) codes

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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