Cell biology of embryo-implantation: unravelling the role of leukaemia inhibitory factor
AA Fouladi Nashta1, G Schofield1, CV Andreu1, N Nijjar1, AG Smith2, JK Heath3 & SJ Kimber1
Many of the functions of ovarian steroids in regulating embryo-implantation occur through the actions of cytokines and growth factors on the uterus. One such cytokine, Leukaemia Inhibitory factor (LIF), is critical for implantation in a range of mammalian species. LIF is expressed transiently in the murine glandular uterine epithelium (GE) on day 1 and then day 4 of pregnancy (day of implantation) induced by estrogen. Female mice lacking a functional LIF gene cannot support embryo-implantation (Stewart et al 1992, Nature 359,79) although LIF-null embryos implant in wild type uteri. This suggests that LIF is primarily essential for uterine function, although it may also be trophic for the embryo. The uteri of LIF-null female mice do not undergo decidualisation, the process of differentiation of the uterine stroma for implantation. Decidualisation requires embryonic signal(s) and is promoted by prostaglandins. We investigated the role of LIF by a combination of in vitro experiments and analysis of molecular expression in LIF-null mice. We found that there are multiple targets for LIF in the uterus. LIF affected stromal cell numbers, including those of leukocytes, and GE. A number of molecules are mis-regulated in LIF null uteri e.g. H-type-1 antigen in luminal epithelium (LE) and cox-2 and BMPs in stroma. In vitro, LIF, in the presence of 2% serum inhibited stromal differentiation without affecting prostaglandin synthesis. While in semi-polarised LE-cultures, LIF increased IL-1-alpha secretion. Thus LIF can induce secretion by LE of a decidualisation-promoter(IL-1alpha), while acting directly on stromal cells to inhibit their differentiation. Our hypothesis is that a critical balance between LE IL-1alpha and GE LIF regulates whether stromal cells respond to blastocyst signals to differentiate.