WNT/β-catenin pathway up-regulates Stat3 and converges on LIF to prevent differentiation of mouse embryonic stem cells

Abstract

Embryonic stem (ES) cells rely on growth factors provided by feeder cells or exogenously to maintain their pluripotency. In order to identify such factors, we have established sub-lines of STO feeder cells which exhibit variable ability in supporting ES cell self-renewal. Functional screening identifies WNT5A and WNT6 as STO cell-produced factors that potently inhibit ES cell differentiation in a serum-dependent manner. Furthermore, direct activation of beta-catenin without disturbing the upstream components of the WNT/beta-catenin pathway fully recapitulates the effect of WNTs on ES cells. Importantly, the WNT/beta-catenin pathway up-regulates the mRNA for Stat3, a known regulator of ES cell self-renewal in the mouse. Finally, LIF is able to mimic the serum effect to act synergistically with WNT proteins to inhibit ES cell differentiation. Therefore, our study reveals part of the molecular mechanisms by which the WNT/beta-catenin pathway acts to prevent ES cell differentiation through convergence on the LIF/JAK-STAT pathway at the level of STAT3.

β-Catenin up-regulates Nanog expression through interaction with Oct-3/4 in embryonic stem cells

“…Furthermore, several studies, including ours, suggest that β-catenin plays an important role in the self-renewal of ES cells [12,13]. Establishment of β-catenin-null ES cells, however, has also been reported [23].…”

“…It is reported that activation of β-catenin leads to induction of STAT3 mRNA in ES cells [12]. Involvement of c-myc, a direct target molecule of β-catenin, in the self-renewal of ES cells has been demonstrated [24].…”

“…Interestingly, Sato et al have demonstrated that activation of the Wnt pathway by a glycogen synthase kinase (GSK)-3-specific pharmacological inhibitor, Bio, results in the maintenance of self-renewal in both mouse and human ES cells [11]. Moreover, the conditioned medium from mouse fibroblasts expressing Wnt can maintain the pluripotency of mouse ES cells [12][13][14]. These observations suggest the involvement of the Wnt pathway in ES cell self-renewal and raised the possibility that β-catenin, a component of the Wnt signaling pathway, might play some role in the LIF-dependent self-renewal of ES cells, as in the case of adenomatous polyposis coli (APC) [15].…”

The ground state of embryonic stem cell self-renewal

“…2f). Therefore elevated c-Myc is not necessary for ES-cell propagation, although some requirement for basal Myc activity is not excluded.STAT3 signalling is central to previous models of ES-cell self-renewal 8,21 and has also been implicated in effects of BIO 20,22,23 . In 3i, however, we do not detect activation of STAT3 or induction of its target SOCS3 (Supplementary Information).…”

“…STAT3 signalling is central to previous models of ES-cell self-renewal 8,21 and has also been implicated in effects of BIO 20,22,23 . In 3i, however, we do not detect activation of STAT3 or induction of its target SOCS3 (Supplementary Information).…”