Abstract
Mouse pluripotent stem cells (PSCs), such as ES cells and induced PSCs (iPSCs), are an excellent system to investigate the molecular and cellular mechanisms involved in early embryonic development. The signaling pathways orchestrated by leukemia inhibitor factor/STAT3, Wnt/β-catenin, and FGF/MEK/ERK play key roles in the generation of pluripotency. However, the function of TGF-β signaling in this process remains elusive. Here we show that inhibiting TGF-β signaling with its inhibitor SB431542 can substitute for Oct4 during reprogramming. Moreover, inhibiting TGF-β signaling can sustain the pluripotency of iPSCs and ES cells through modulating FGF/MEK/ERK signaling. Therefore, this study reveals a novel function of TGF-β signaling inhibition in the generation and maintenance of PSCs.
Highlights
Pluripotent stem cells (PSCs) have been used widely to study molecular mechanisms involved in early embryo development
We showed that the inhibition of TGF- signaling by SB431542 (SB43), a small molecule, can substitute for Oct4 to reprogram mouse embryonic fibroblasts (MEFs) into induced PSCs (iPSCs)
The other group of cells was grown in serum-containing medium supplemented with VPA as the control. 24 days after induction, many AP-positive colonies were observed in the control serum/VPA medium, but AP-positive colonies were barely detectable under VPC conditions (Fig. 1, A and B). These data suggest that PD03 and CHIR are not sufficient to promote the generation of iPSCs from MEFs under serum-free conditions
Summary
Pluripotent stem cells (PSCs) have been used widely to study molecular mechanisms involved in early embryo development. Conclusion: TGF- signaling inhibition promotes generation and maintenance of PSCs. Significance: Our study reveals a novel function of TGF- signaling in the generation of PSCs. Mouse pluripotent stem cells (PSCs), such as ES cells and induced PSCs (iPSCs), are an excellent system to investigate the molecular and cellular mechanisms involved in early embryonic development. Somatic cells transduced with the reprogramming factors often fail to be fully reprogrammed, but these intermediate cells can be reprogrammed to complete iPSCs in serum-free medium [8] Under this condition, FGF/ MEK/ERK signaling inhibition by PD03 induces the transition to complete pluripotency, but Wnt signaling activation by CHIR alone has no discernible effect [8]. Mechanistic studies show that TGF- signaling inhibition can modulate the FGF/ MEK/ERK pathway through reducing ERK phosphorylation in ES cells
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