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Lack of Aicda-mediated Suppression of Fgf/Erk Signaling Inhibits Naïve Pluripotency

Review ofActivation-Induced Cytidine Deaminase Regulates Fibroblast Growth Factor/Extracellular Signal-Regulated Kinases Signaling to Achieve the Naïve Pluripotent State During Reprogrammingfrom STEM CELLS by Stuart P. Atkinson 

Fascinating research from the laboratories of Ritu Kumar and Todd Evans (Weill Cornell Medicine, New York, USA) recently established that activation‐induced cytidine deaminase (Aicda), an APOBEC family enzyme with cytosine deamination activity [1], facilitated the efficient erasure of epigenetic memory (DNA demethylation) during late stages of the reprogramming of somatic cells into murine induced pluripotent stem cells (iPSCs) [2]. While this study discovered that while only a proportion of Aicda-null iPSCs could be maintained and stabilized in culture, two subsequent studies appear to contradict this finding [3, 4]. To explore the disparity between these studies, the authors now return with a new STEM CELLS article in which they report that while stable reprogramming can occur without the presence of Aicda, resultant mouse iPSCs fail to achieve naïve pluripotency [5].

The authors discovered that Aicda-null mouse iPSCs remain distinct from wild‐type iPSCs as they failed to achieve the naïve pluripotent state and appear similar to mouse epiblast-derived stem cells. Aicda-null mouse iPSCs displayed a distinct morphology, expressed lower levels of pluripotency-associated genes and higher levels of differentiation-associated genes, displayed elevated genomic instability, and remained primed for differentiation due to a failure to adequately suppress fibroblast growth factor/extracellular signal‐regulated kinase (Fgf/Erk) signaling [6]. Interestingly, Aicda-null iPSCs displayed marked genomic hypermethylation, suggesting that the suppression of Fgf/Erk signaling by Aicda occurs independently of deaminase activity.

Overall, the authors establish Aicda-mediated suppression of Fgf/Erk signaling as a novel mechanism controlling naïve pluripotency in mouse iPSCs, and in doing so, they may have provided an understanding of how we may properly stabilize the ground state pluripotent cells employed for disease modeling and cellular therapies.

For more on naïve pluripotency, the role of Aicda, and more, stay tuned to the Stem Cells Portal! 

References

  1. Bhutani N, Brady JJ, Damian M, et al., Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature 2009;463:1042.
  2. Kumar R, DiMenna L, Schrode N, et al., AID stabilizes stem-cell phenotype by removing epigenetic memory of pluripotency genes. Nature 2013;500:89.
  3. Habib O, Habib G, Do JT, et al., Activation-Induced Deaminase-Coupled DNA Demethylation Is Not Crucial for the Generation of Induced Pluripotent Stem Cells. Stem Cells and Development 2013;23:209-218.
  4. Shimamoto R, Amano N, Ichisaka T, et al., Generation and Characterization of Induced Pluripotent Stem Cells from Aid-Deficient Mice. PLOS ONE 2014;9:e94735.
  5. Kumar R and Evans T, Activation-Induced Cytidine Deaminase Regulates Fibroblast Growth Factor/Extracellular Signal-Regulated Kinases Signaling to Achieve the Naïve Pluripotent State During Reprogramming. STEM CELLS 2019;37:1003-1017.
  6. Ying Q-L, Wray J, Nichols J, et al., The ground state of embryonic stem cell self-renewal. Nature 2008;453:519.