Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3
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Date
1998Author
Niwa, Hitoshi
Burdon, Tom
Chambers, Ian
Smith, Austin G
Metadata
Abstract
The propagation of embryonic stem (ES) cells in an undifferentiated pluripotent state is dependent on
leukemia inhibitory factor (LIF) or related cytokines. These factors act through receptor complexes containing
the signal transducer gp130. The downstream mechanisms that lead to ES cell self-renewal have not been
delineated, however. In this study, chimeric receptors were introduced into ES cells. Biochemical and
functional studies of transfected cells demonstrated a requirement for engagement and activation of the latent
trancription factor STAT3. Detailed mutational analyses unexpectedly revealed that the four STAT3 docking
sites in gp130 are not functionally equivalent. The role of STAT3 was then investigated using the dominant
interfering mutant, STAT3F. ES cells that expressed this molecule constitutively could not be isolated. An
episomal supertransfection strategy was therefore used to enable the consequences of STAT3F expression to
be examined. In addition, an inducible STAT3F transgene was generated. In both cases, expression of STAT3F
in ES cells growing in the presence of LIF specifically abrogated self-renewal and promoted differentiation.
These complementary approaches establish that STAT3 plays a central role in the maintenance of the
pluripotential stem cell phenotype. This contrasts with the involvement of STAT3 in the induction of
differentiation in somatic cell types. Cell type-specific interpretation of STAT3 activation thus appears to be
pivotal to the diverse developmental effects of the LIF family of cytokines. Identification of STAT3 as a key
transcriptional determinant of ES cell self-renewal represents a first step in the molecular characterization of
pluripotency.