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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!


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