Abstract
Regulation of angiogenesis in the utero-placental bed determines adequate trophoblast invasion, placenta formation and development, as well as successful course of pregnancy. Natural killer (NK) cells, macrophages and trophoblast have the most significant effect on angiogenesis. To date, the functions of cells participating in placenta formation have been described in detail, both individually (in vitrо) and in tissues (in situ). However, no models have yet been created that reflect the interactions of NK cells, trophoblast and endothelium during angiogenesis. It remains unclear, how each cell population contributes to placental angiogenesis regulation, and to the cross-regulation of participating cell functions. Therefore, the aim of this research was to study contact and distant effects of NK cells upon formation of tube-like structures through co-culture of endothelial and trophoblast cells influenced by various cytokines (bFGF, VEGF, PlGF, TGF-β, IL-8, IFNγ and IL-1β). Introduction of NK cells to the co-culture of endothelial and trophoblast cells under conditions of both contact and distance-dependent culturing did not change the length of tube-like structures formed by endothelial cells. During contact-dependent culturing of NK cells with co-culture of endothelial and trophoblast cells in presence of IL-1β, the length of tubule-like structures remained unchanged, compared with the length of tube-like structures formed under the same culturing conditions, but without the cytokine added. During distant culturing of NK cells with co-culture of endothelial and trophoblast cells in the presence of IL-1β, the length of tube-like structures increased as compared with those formed under the same culturing conditions but without the cytokine. During contact-dependent (but not distant) culturing of NK cells with the co-culture of endothelial and trophoblast cells in the presence of VEGF, the length of tube-like structures was greater than those formed under the same culturing conditions but without the cytokine. When used in a three-component cell system, the pro-inflammatory cytokine IFNγhad no effect upon angiogenesis. During distant (but not contact-dependent) culturing of NK cells with co-culture of endothelial and trophoblast cells in the presence of TGF-β, the length of tube-like structures was less than the length of tube-like structures formed under the same culturing conditions but without the cytokine. Under conditions of distant culturing, TGF-βtriggered a signal in NK cells that inhibited angiogenesis. Decreased length of tube-like structures under conditions of a three-component cell co-culture in the presence of the following pro-angiogenic factors was revealed: IL-8, PlGF (during contact-dependent culturing only) and bFGF (during both contact-dependent and distant culturing). Thus, the effects of cytokines upon angiogenesis in a three-component co-culture (NK cells, trophoblast and endothelium) differed from those revealed previously in single-component (endothelium only) and two-component (co-culture of endothelium and trophoblast) cell models. The results of these experiments indicated that regulation of placental cell interactions involved both cellular contacts and effects produced by cytokines.
Highlights
Placenta formation is a coordinated process that requires participation of a variety of cell populations on both the fetal and maternal sides
During contact-dependent culturing of endothelial cells and trophoblast cells of the JEG-3 cell line with Natural killer (NK) cells in the presence of bFGF 10 ng/ml, the length of tube-like structures decreased compared with the length of tube-like structures formed under the same culturing conditions but without bFGF (Figure 3)
Under conditions of contact-dependent culturing, trophoblast cells expressing the HLA-C and HLA-G molecules on their surface change the functional properties of NK cells [60, 84], while suppressing their cytotoxic function
Summary
Placenta formation is a coordinated process that requires participation of a variety of cell populations on both the fetal and maternal sides. They participate in regulation of immune cell function and in formation of immunological tolerance during pregnancy. During contact-dependent culturing of endothelial cells and trophoblast cells of the JEG-3 cell line with NK cells in the presence of bFGF 10 ng/ml, the length of tube-like structures decreased compared with the length of tube-like structures formed under the same culturing conditions but without bFGF (Figure 3). During distant culturing of endothelial cells and cells of the JEG-3 cell line with NK cells in the presence of bFGF, the length of tube-like structures decreased at all concentrations of bFGF compared with the length of tube-like structures formed under the same culturing conditions but without addition of the cytokine. The length of tube-like structures formed during distant culturing of endothelial cells and cells of the JEG-3 cell line with NK cells in the presence of VEGF remained unchanged compared with the length formed under the same culturing conditions but without the growth factor
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