Abstract
Human induced pluripotent stem cells (iPSCs) can be divided into a leukemia inhibitory factor (LIF)-dependent naïve type and a basic fibroblast growth factor (bFGF)-dependent primed type. Although the former are more undifferentiated than the latter, they require signal transduction inhibitors and sustained expression of the transgenes used for iPSC production. We used a transcriptionally enhanced version of OCT4 to establish LIF-dependent human iPSCs without the use of inhibitors and sustained transgene expression. These cells belong to the primed type of pluripotent stem cell, similar to bFGF-dependent iPSCs. Thus, the particular cytokine required for iPSC production does not necessarily define stem cell phenotypes as previously thought. It is likely that the bFGF and LIF signaling pathways converge on unidentified OCT4 target genes. These findings suggest that our LIF-dependent human iPSCs could provide a novel model to investigate the role of cytokine signaling in cellular reprogramming.
Highlights
Mouse pluripotent stem cells can be divided into naıve and primed pluripotent cells, depending on their level of pluripotency, patterns of gene expression, and the cytokines required to maintain an undifferentiated state [1,2,3,4,5]
Naıve pluripotent stem cells, represented by embryonic stem cells (ESCs) and standard induced pluripotent stem cells (iPSCs), typically require a combination of leukemia inhibitory factor (LIF) and BMP 2 or BMP4 for self-renewal, whereas primed pluripotent stem cells, such as epiblast stem cells (EpiSCs) [6,7], require basic fibroblast growth factor (bFGF) and transforming growth factor b/ activin A signaling for self-renewal
ESC-like colonies were defined as iPSC colonies when they were double-positive for the pluripotency markers NANOG and TRA1-60 (Fig. 1A)
Summary
Mouse pluripotent stem cells can be divided into naıve and primed pluripotent cells, depending on their level of pluripotency, patterns of gene expression, and the cytokines required to maintain an undifferentiated state (self-renewal) [1,2,3,4,5]. Human ESCs and iPSCs appear to be primed pluripotent stem cells [1,2,3,4,5]. LIF-dependent human ESCs and iPSCs have characteristics of naıve stem cells; they require for self-renewal chemical inhibitors against cell signaling pathways and sustained expression of the transgenes used to establish iPSCs unlike their mouse counterparts [13,14,15,16].
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