Leukaemia inhibitory factor and the regulation of pre‐implantation development of the mammalian embryo

Abstract

This paper reviews the evidence that certain growth factors, particularly leukaemia inhibitory factor (LIF), play a crucial role in regulating the development of the pre-implantation mammalian embryo. LIF was originally implicated in regulating the early development of the mouse embryo because it inhibited the differentiation of embryonic stem (ES) cells, pluripotential cells derived from the inner cell mass of the blastocyst. Subsequent studies on its role in vivo revealed, surprisingly, that it is essential for the growth rather than the differentiation of the blastocyst. In vivo, overtly normal blastocysts can be produced in a LIF-deficient environment that are capable of forming viable fertile adults. However, in the absence of LIF, they fail to implant and enter into a state resembling that exhibited by blastocysts undergoing delayed implantation, which is characterized by a cessation of cell proliferation. This failure to implant occurs because the principle sites of LIF production are the endometrial glands of the uterus. These synthesize and secrete LIF at implantation, with LIF synthesis essential for implantation. Preliminary evidence indicates that LIF synthesis is required both by the uterus for it to undergo decidualization and by the blastocyst for implantation. These data indicate that the maternal environment plays a crucial role in the development and growth of the pre-implantation embryo, by supplying factors that regulate these processes in the embryo.

STAT signaling is active during early mammalian development

“…Whether this is due to the action of LIF directly on the blastocyst or that of a paracrine activation of gene expression in the surrounding maternal tissue has not yet been proven. However, consistent with the latter proposal, LIF 2/2 females mated with vasectomized males were unable to undergo an induced decidual reaction, where uterine stromal cells proliferate and differentiate to produce a decidual mass (Stewart, 1994). Because Stat3 is activated in response to LIF and because we have demonstrated the presence of active Stat3 in the decidua, it is likely that Stat3 plays an important role during decidualization and for the provision of a suitable maternal environment for the development of the early postimplantation embryo.…”

Effects of gas atmosphere, platelet-derived growth factor and leukemia inhibitory factor on cell numbers of rabbit embryos cultured in a protein-free medium

“…Other investigators, however, have not observed a beneficial effect of PDGF on development of mouse embryos (Colver et al, 1991 ) or cow embryos (Flood et al, 1993). The LIF, a glycoprotein expressed on cultured mouse blastocysts (Murray et al, 1990) and in the uterine endometrial glands of mice by the fourth day of pregnancy, is maternally controlled and is essential for implantation (reviewed by Stewart, 1994). The addition of human LIF (hLIF) to the culture medium increased the number of eight-cell stage mouse embryos which hatched and increased the size of blastocyst outgrowths in vitro (Robertson et al, 1991;Lavranos et al, 1995).…”

The Tissue Specific Role of Estrogen and Progesterone in Human Endometrium and Mammary Gland

“…However, today there are already some biomarkers confirmed in separate studies which are pivotial during implantation process. For example, the most potential endometrial marker identified is leukemia inhibitory factor (LIF) and its importance has been proven in animal and human studies (Stewart et al, 1994;Arici et al, 1995;Steck et al, 2004). Unfortunately, the development of recombinant human LIF (r-fLIF) has not met the expectations of increasing implantation rates in infertile women (Brinsden et al, 2009).…”