Insulin-like growth factor I and II regulate the life cycle of trophoblast in the developing human placenta

Abstract

The main disorders of human pregnancy are rooted in defective placentation. Normal placental development depends on proliferation, differentiation, and fusion of cytotrophoblasts to form and maintain an overlying syncytiotrophoblast. There is indirect evidence that the insulin-like growth factors (IGFs), which are aberrant in pregnancy disorders, are involved in regulating trophoblast turnover, but the processes that control human placental growth are poorly understood. Using an explant model of human first-trimester placental villus in which the spatial and ontological relationships between cell populations are maintained, we demonstrate that cytotrophoblast proliferation is enhanced by IGF-I/IGF-II and that both factors can rescue cytotrophoblast from apoptosis. Baseline cytotrophoblast proliferation ceases in the absence of syncytiotrophoblast, although denuded cytotrophoblasts can proliferate when exposed to IGF and the rate of cytotrophoblast differentiation/fusion and, consequently, syncytial regeneration, increases. Use of signaling inhibitors suggests that IGFs mediate their effect on cytotrophoblast proliferation/syncytial formation through the MAPK pathway, whereas effects on survival are regulated by the phosphoinositide 3-kinase pathway. These results show that directional contact between cytotrophoblast and syncytium is important in regulating the relative amounts of the two cell populations. However, IGFs can exert an exogenous regulatory influence on placental growth/development, suggesting that manipulation of the placental IGF axis may offer a potential therapeutic route to the correction of inadequate placental growth.

Macrophage-Derived IL-33 Is a Critical Factor for Placental Growth

“…However, little is known about the source and nature of signals regulating trophoblast proliferation. Although no data exist to identify a paracrine signal regulating proliferation of CCTs, there is evidence that placental stromal cells secrete IGF1 to trigger vCTB proliferation (42,58). Interestingly, we detected Placental explants (7-9th week) were stimulated with IL-33 (100 ng/ml) for 2 h, followed by fixation.…”

“…The total extent of EVT formation in control-treated explant cultures reached a 3.8-fold gain at day 3, whereas addition of 100 ng/ml IL-33 provoked a 5-fold increase when compared with respective untreated explants at day 0. Insulin-like growth factor (IGF)2, a trigger of trophoblast proliferation (42) and motility (43), was used as positive control. To separately study the effect of IL-33 on proliferative and invasive trophoblast subtypes, we performed invasion assays using growtharrested primary trophoblasts, which were routinely tested for specific EVT marker expression (Fig.…”

Adhesion Molecules in Human Trophoblast – A Review. I. Villous Trophoblast

“…Signalling through α6β4 can activate the protein tyrosine phosphatase SHP-2, in turn activating the phosphatidylinositol 3-kinase/Akt pathway [12,13], which is important in CTB proliferation in the placental villus [14,15].…”

Evolutionary genetics and implications of small size and twinning in callitrichine primates

“…Numerous IGF1R mutations are associated with both late prenatal and early postnatal growth restriction in humans (62,63), and mutations of IGF1R in mice have been demonstrated to slow embryonic growth (64). IGF2 is the primary growth factor controlling placental development and growth and is also critical in early embryonic growth (65)(66)(67)(68). The IGFBPs are a family of proteases that bind with high affinity to the IGFs, serving to prolong their half-life and modulate availability and function with notable impacts on developmental growth and metabolism (49).…”