Hes1 Desynchronizes Differentiation of Pluripotent Cells by Modulating STAT3 Activity

Abstract

Robust development of the early embryo may benefit from mechanisms that ensure that not all pluripotent cells differentiate at exactly the same time: such mechanisms would build flexibility into the process of lineage allocation. This idea is supported by the observation that pluripotent stem cells differentiate at different rates in vitro. We use a clonal commitment assay to confirm that pluripotent cells commit to differentiate asynchronously even under uniform differentiation conditions. Stochastic variability in expression of the Notch target gene Hes1 has previously been reported to influence neural versus mesodermal differentiation through modulation of Notch activity. Here we report that Hes1 also has an earlier role to delay exit from the pluripotent state into all lineages. The early function of Hes1 to delay differentiation can be explained by an ability of Hes1 to amplify STAT3 responsiveness in a cell-autonomous manner. Variability in Hes1 expression therefore helps to explain why STAT3 responsiveness varies between individual ES cells, and this in turn helps to explain why pluripotent cells commit to differentiate asynchronously. Stem Cells 2013;31:1511–1522

Pwp1 Is Required for the Differentiation Potential of Mouse Embryonic Stem Cells Through Regulating Stat3 Signaling

“…Zap70 KD results in not only severe defects with retinoic acid treatment in vitro but also defective teratoma formation in vivo [57]. By enhancing Stat3 activity, Hes1 also delays mESC differentiation [58]. Consistently, our results demonstrated that upregulation of Stat3 resulted in severe developmental defects, whereas when Stat3 was knocked down with siStat3 or when Stat3 activation was selectively inhibited, the Pwp1 KD cells regained their differentiation potential.…”

Linc1557 is critical for the initiation of embryonic stem cell differentiation by directly targeting the LIF/STAT3 signaling pathway

“…The LIF/STAT3 signaling pathway has been reported to be essential for maintaining the self‐renewal and pluripotency of mouse ESCs. Active STAT3 can target ESC self‐renewal‐ and differentiation‐related genes, whereas HES1 can enhance STAT3 activity and delay mouse ESC differentiation . LncRNAs, with rich information and diverse regulatory mechanisms, have been demonstrated as important epigenetic regulators in maintaining mouse ESC pluripotency .…”

“…Active STAT3 can target ESC selfrenewal-and differentiation-related genes, 22 whereas HES1 can enhance STAT3 activity and delay mouse ESC differentiation. 20 LncRNAs, with rich information and diverse regulatory mechanisms, have been demonstrated as important epigenetic regulators in maintaining mouse ESC pluripotency. 5 However, whether lncRNAs directly target the LIF/STAT3 signaling pathway and regulate ESC differentiation needs further investigation.…”

“…The leukemia inhibitory factor (LIF)/signal transducer and activator of transcription 3 (STAT3) signaling pathway has a critical biological function in mouse ESC self‐renewal and differentiation. LIF is originally identified as an important cytokine that activates STAT3 and is critical for the maintenance of mouse ESC pluripotency . After its activation via phosphorylation in the cytoplasm, the STAT3 protein enters the cell nucleus to bind response elements and regulates the expression of target genes.…”

“…LIF is originally identified as an important cytokine that activates STAT3 and is critical for the maintenance of mouse ESC pluripotency. [19][20][21] After its activation via phosphorylation in the cytoplasm, the STAT3 protein enters the cell nucleus to bind response elements and regulates the expression of target genes. In addition, STAT3 can directly target the promoters of particular key genes that constitute the core pluripotency network 22 and maintain mouse ESCs in the pluripotent state by inhibiting mesodermal and endodermal differentiation.…”