Regulation of embryonic stem cell self-renewal and pluripotency by leukaemia inhibitory factor

Abstract

LIF (leukaemia inhibitory factor) is a key cytokine for maintaining self-renewal and pluripotency of mESCs (mouse embryonic stem cells). Upon binding to the LIF receptor, LIF activates three major intracellular signalling pathways: the JAK (Janus kinase)/STAT3 (signal transducer and activator of transcription 3), PI3K (phosphoinositide 3-kinase)/AKT and SHP2 [SH2 (Src homology 2) domain-containing tyrosine phosphatase 2]/MAPK (mitogen-activated protein kinase) pathways. These pathways converge to orchestrate the gene expression pattern specific to mESCs. Among the many signalling events downstream of the LIF receptor, activation and DNA binding of the transcription factor STAT3 plays a central role in transducing LIF's functions. The fundamental role of LIF for pluripotency was highlighted further by the discovery that LIF accelerates the conversion of epiblast-derived stem cells into a more fully pluripotent state. In the present review, we provide an overview of the three major LIF signalling pathways, the molecules that interact with STAT3 and the current interpretations of the roles of LIF in pluripotency.

Figure 1. Domain structures of STAT3 and JAK1

Amino acid numbers are shown above each rectangle.

Figure 2. LIF/JAK/STAT3 signalling pathway

Figure 3. Three inhibitory mechanisms of the LIF/JAK/STAT3 pathway

(A) Inhibition of JAK1 and STAT3 by SHP, PTP1B and PTP-BL. (B) Inhibition of STAT3 by PIAS. (C) Inhibition of JAK1 by SOCS1 and SOCS3.

Figure 4. LIF/PI3K/AKT signalling pathway

Ac, acetylation.

Figure 5. LIF/SHP2/MAPK signalling pathway

Figure 6. Self-renewal using cytokines (LIF and BMP) or chemical inhibitors

(A) Inhibition of differentiation by LIF and BMP. (B) Inhibition of differentiation by 3i. (C) Inhibition of differentiation by 2i.

Figure 7. Embryonic sources of mESCs and mEpiSCs