The Role of the Leukemia Inhibitory Factor (LIF) — Pathway in Derivation and Maintenance of Murine Pluripotent Stem Cells

Abstract

Developmental biology, regenerative medicine and cancer biology are more and more interested in understanding the molecular mechanisms controlling pluripotency and self-renewal in stem cells. Pluripotency is maintained by a synergistic interplay between extrinsic stimuli and intrinsic circuitries, which allow sustainment of the undifferentiated and self-renewing state. Nevertheless, even though a lot of efforts have been made in the past years, the precise mechanisms regulating these processes remain unclear. One of the key extrinsic factors is leukemia inhibitory factor (LIF) that is largely used for the cultivation and derivation of mouse embryonic and induced pluripotent stem cells. LIF acts through the LIFR/gp130 receptor and activates STAT3, an important regulator of mouse embryonic stem cell self-renewal. STAT3 is known to inhibit differentiation into both mesoderm and endoderm lineages by preventing the activation of lineage-specific differentiation programs. However, LIF activates also parallel circuitries like the PI3K-pathway and the MEK/ERK-pathway, but its mechanisms of action remain to be better elucidated. This review article aims at summarizing the actual knowledge on the importance of LIF in the maintenance of pluripotency and self-renewal in embryonic and induced pluripotent stem cells.

Leukemia inhibitory factor (LIF)

“…These cells can be induced by the forced expression of key transcriptional factors (including Oct3/4, SOX2, c-Myc and Klf4) [70] and both the induction of the pluripotency transcriptional network [71] and the survival/self-renewal of iPSCs [72] was dependent on LIF or or LIF-like signalling.…”

The role of the leukemia inhibitory factor receptor in neuroprotective signaling

“…The precise consequences of each signaling pathway differ between cell types, but one of the ways in which LIFR signaling exerts long-lasting effects is through changes in gene expression. In several embryonic stem cell lines, Ras/MAPK signaling upregulates genes involved in proliferation and self-renewal, JAK/STAT controls genes that regulate self-renewal, and PI3K/Akt signaling induces pro-survival genes (Binetruy, Heasley, Bost, Caron, & Aouadi, 2007; Graf, Casanova, & Cinelli, 2011; Majumder et al, 2012). …”

Female Tract Cytokines and Developmental Programming in Embryos

“…The key role of maternal, as opposed to embryo-derived, LIF is indicated by observations in Lif null mice, where injecting LIF on the day of implantation rescues fertility, while LIF deficient embryos are not developmentally compromised, but implant and develop successfully in wild-type mice (Stewart et al 1992). LIF receptor (LIFR) is expressed in preimplantation embryos, predominantly from the blastocyst stage of development (Charnock-Jones et al 1994;Nichols et al 1996;Sharkey et al 1995), and LIF ligation of the LIFR/gp130 complex activates the MAPK and PI3K pathways as well as JAK/STAT3 pathways in embryonic cells (Graf et al 2011).…”