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Can Newly Identified Transcription Factors Improve iPSC Reprogramming?

Review of "Identification of potential transcription factors that enhance human iPSC generation" from Scientific Reports by Stuart P. Atkinson

While a range of somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) via the ectopic expression of a small number of factors, such as OCT4, SOX2, KLF4, and MYC [1, 2], the process remains inefficient [3]. Furthermore, cellular phenotypes and mutations associated with different diseases can negatively influence the reprogramming process [4]; therefore, many have sought novel means of improving this process in healthy and diseased cells.

In a recent study from the laboratories of Mohamed M. Emara (Qatar University) and Sara A. Abdulla (Hamad Bin Khalifa University, Doha, Qatar), researchers hoped to define factors that regulate the reprogramming of cells isolated from Parkinson's Disease patients. As reported in their most recent article [5], Swaidan et al. now establish that regulating the expression of GBX2, NANOGP8, SP8, PEG3, and ZIC1 may represent a means to improve the generation of iPSCs.

The authors studied the reprogramming process using dermal fibroblasts isolated from familial and sporadic Parkinson's disease patients using an RNA-sequencing platform and noted the altered expression of a range of genes in fully reprogrammed iPSC colonies that appeared to enhance the process. Specifically, the authors sought to understand why one of the Parkinson's disease cell samples reprogrammed at a higher rate when compared to other patient samples and healthy controls.

Identified and validated transcription factors whose overexpression correlated with increased reprogramming included GBX2 (Gastrulation Brain Homeobox 2), SP8, ZIC1, and NANOGP8 (Nanog Homeobox Retrogene P8), while PEG3 (Paternally-expressed gene 3) repression associated with improved reprogramming. Of note, previous studies had indicated a pluripotency-related function for GBX2 [6], ZIC1 [7], SP8 [8], and PEG3 [9], thereby providing credence to these findings. Fascinatingly, the study also revealed that these transcription factors played crucial roles in maintaining pluripotency/self-renewal and interacted with key members of the pluripotent transcription factor network, such as OCT4, SOX2, NANOG, and KLF4.

In summary, the authors believe that the modulated expression of these transcription factors may permit increased efficiency reprogramming of somatic cells from healthy and diseased patients when used alongside traditional reprogramming strategies; however, they do point to the need to fully understand the mechanisms of action of these factors during the reprogramming process.

For more on the transcription factors that may improve iPSC reprogramming and bring their progeny closer to therapeutic applications, stay tuned to the Stem Cells Portal!

References

  1. Takahashi K, Tanabe K, Ohnuki M, et al., Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors. Cell 2007;131:861-872.
  2. Takahashi K and Yamanaka S, Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell 2006;126:663-676.
  3. Karagiannis P, Takahashi K, Saito M, et al., Induced Pluripotent Stem Cells and Their Use in Human Models of Disease and Development. Physiological Reviews 2018;99:79-114.
  4. Hayashi Y, Human mutations affecting reprogramming into induced pluripotent stem cells. AIMS Cell and Tissue Engineering 2017;1:31-46.
  5. Swaidan NT, Salloum-Asfar S, Palangi F, et al., Identification of potential transcription factors that enhance human iPSC generation. Scientific Reports 2020;10:21950.
  6. Tai C-I and Ying Q-L, Gbx2, a LIF/Stat3 target, promotes reprogramming to and retention of the pluripotent ground state. Journal of Cell Science 2013;126:1093.
  7. Bogliotti YS, Wu J, Vilarino M, et al., Efficient derivation of stable primed pluripotent embryonic stem cells from bovine blastocysts. Proceedings of the National Academy of Sciences 2018;115:2090.
  8. Xu Z, Robitaille AM, Berndt JD, et al., Wnt/beta-catenin signaling promotes self-renewal and inhibits the primed state transition in naive human embryonic stem cells. Proc Natl Acad Sci U S A 2016;113:E6382-E6390.
  9. Theka I, Sottile F, Aulicino F, et al., Reduced expression of Paternally Expressed Gene-3 enhances somatic cell reprogramming through mitochondrial activity perturbation. Scientific Reports 2017;7:9705.