Abstract
Induction of pluripotent stem cells (iPSC) by OCT4 (octamer-binding transcription factor 4), SOX2 (SR box 2), KLF4 (Krüppel-Like Factor 4), and MYC (cellular Myelocytomatosis, c-MYC or MYC) (collectively OSKM) is revolutionary, but very inefficient, slow, and stochastic. It is unknown as to what underlies the potency aspect of the multi-step, multi-pathway, and inefficient iPSC reprogramming. Mesenchymal-to-epithelial (MET) transition is known as the earliest pathway reprogrammed. Using the recently established concepts of reprogramome and reprogramming legitimacy, the author first demonstrated that ribosome biogenesis (RB) is globally enriched in terms of human embryonic stem cells in comparison with fibroblasts, the popular starting cells of pluripotency reprogramming. It is then shown that the RB network was reprogrammed quickly in a coordinated fashion. Human iPSCs also demonstrated a more robust ribosome biogenesis. The quick and global reprogramming of ribosome biogenesis was also observed in an independent fibroblast line from a different donor. This study additionally demonstrated that MET did not initiate substantially at the time of proper RB reprogramming. This quick, coordinated and authentic RB reprogramming to the more robust pluripotent state by the OSKM reprogramming factors dramatically contrasts the overall low efficiency and long latency of iPSC reprogramming, and aligns well with the potency aspect of the inefficient OSKM reprogramming.
Highlights
Human pluripotent stem cells (PSCs) can be induced by ectopic expression of four factors, OCT4, SOX2, KLF4, and MYC in somatic cells, most commonly fibroblasts [1,2,3].Induction of PSCs from human fibroblasts is still very inefficient, slow, and stochastic [4,5,6,7].Our understanding about the molecular events underlying the mixed outcomes of Induction of pluripotent stem cells (iPSC) generation is very rudimentary
Using RNA sequencing (RNA-seq) and the concept of reprogramming legitimacy, this study demonstrated that ribosome biogenesis (RB) pathways were properly reprogrammed to the pluripotent state in a highly coordinated manner as early as 48 h post-transduction of OSKM in human fibroblasts
The author recently reported that ribosome biogenesis (Gene Ontology (GO) #0042254) is among the list of the top GO terms for the genes that have already been properly upreprogrammed to the pluripotent state within 48 h post-transduction of the Yamanaka reprogramming factors
Summary
Human pluripotent stem cells (PSCs) can be induced by ectopic expression of four factors, OCT4, SOX2, KLF4, and MYC (collectively OSKM) in somatic cells, most commonly fibroblasts [1,2,3].Induction of PSCs (iPSCs) from human fibroblasts is still very inefficient, slow, and stochastic [4,5,6,7].Our understanding about the molecular events underlying the mixed outcomes of iPSC generation is very rudimentary. Transcriptional and chromatin-binding data were collected from reprogramming cells, intermediate partially reprogrammed cell lines, and the established iPSC lines [9,10,11,12] These analyses implicitly treated all these transcriptional and binding data as positive responses, partly because scientists were so amazed by this revolutionary technology and apparently ignored the fact that 99% of the data represent the cells that do not go in the direction of pluripotency. Their purified partially reprogrammed cells were heterogenous with limited potentials to be further reprogrammed [10]
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