Expansion of human trophoblastic spheroids is promoted by decidualized endometrial stromal cells and enhanced by heparin-binding epidermal growth factor-like growth factor and interleukin-1β

Abstract

Successful pregnancy in humans depends on deep invasion of the maternal decidua by extravillous trophoblast cells (EVTs), a process regulated by autocrine and paracrine signals in the decidual-trophoblast microenvironment. Here we examined whether trophoblast invasion is affected by decidual differentiation of endometrial stromal cells (ESC) and modulated locally by cytokines and growth factors. Trophoblast spheroids were generated from the EVT-derived cell line AC-1M88 and placed onto monolayers of either undifferentiated or decidualized ESC, or directly onto tissue culture surface. Co-cultures were treated with epidermal growth factor (EGF), hepatocyte growth factor, heparin-binding EGF-like growth factor (HB-EGF), interleukin-1β (IL-1β) and leukaemia inhibitory factor (LIF). Expansion of spheroids over 2-3 days was significantly enhanced by a monolayer of undifferentiated ESC compared with tissue culture surface and further increased if ESC had been decidualized. HB-EGF and IL-1β, alone or in combination with LIF, stimulated spheroid expansion but only on undifferentiated ESC. CEACAM1, an adhesion molecule implicated in trophoblast invasion, was up-regulated in AC-1M88 cells by conditioned medium from decidualized ESC, and by HB-EGF, IL-1β and LIF in combination. Treatment of ESC with HB-EGF or IL-1β increased the level of the tetraspanin CD82, a metastasis suppressor found in decidual cells at the implantation site. We suggest that decidualized ESC support trophoblast invasion by paracrine signals that may include HB-EGF, IL-1β and LIF.

Functional Antagonism between High Temperature Requirement Protein A (HtrA) Family Members Regulates Trophoblast Invasion

“…For example, epithelial-mesenchymal transition is induced in the Ishikawa monolayer treated with ovarian steroids to promote JAR spheroid implantation (25). In response to growth factors and cytokines, CD82 in decidualized T-HESCs and carcinoembryonic antigen-related cell adhesion molecule-1 in AC-1M88 cells (hybridoma cells of primary EVTs and JEG-3 choriocarcinoma cells) are involved in the regulation of T-HESC and AC-1M88 cell migration and invasion (26,27). Our study further revealed a new role of decidual HtrA1 and HtrA3 in antagonizing the function of trophoblastic HtrA4, supporting a novel regulatory mechanism for decidua to modulate trophoblast invasion mediated by the GCM1-HtrA4 axis.…”

CD82 gene suppression in endometrial stromal cells leads to increase of the cell invasiveness in the endometriotic milieu

“…Moreover, our previous work has confirmed that CD82 in decidual stromal cells controls the trophoblasts invasiveness by suppressing integrinb1/mitogen-activated protein kinase (MAPK)/ ERK1/2 signal pathway in human early pregnancy (Li et al 2010). Interestingly, the decidualized ESCs support trophoblasts invasion by paracrine signals, such as HB-EGF, IL1, and LIF, which also can induce CD82 in ESCs for controlling trophoblasts invasion (Gonzalez et al 2011). Since similarity between cancer and endometriosis is valid, it appears feasible to hypothesize that the regulation of CD82 expression occurs in the eutopic endometrium that predisposes to invasion, implantation, adhesion, survival, and growth of ESC in the ectopic milieu.…”

The Human Endometrium as a Sensor of Embryo Quality1

“…Moreover, time-lapse recordings revealed that the stromal cells moved around the embryo to accommodate its expansion [33,34]. Decidualizing stromal cells have been shown to provide a more favorable matrix for trophoblast expansion than do undifferentiated cells [35], indicating that the choreography of stromal cell movement actively assists expansion. Further work showing trophoblast spheroids to expand to a greater extent when cultured on a monolayer of decidualized versus undifferentiated stromal cells provided more evidence supporting directed cell migration as a key element of the decidual phenotype [36].…”