IFPA Award in Placentology lecture: molecular regulation of human trophoblast invasion

Abstract

Invasion of extravillous trophoblast cell types into maternal uterine tissues is essential for successful human placental development and progression of pregnancy. Whereas endovascular trophoblasts migrate into the maternal spiral arteries, interstitial trophoblasts invade the decidual stroma, colonize the vessels from outside and communicate with diverse uterine cell types such as decidual stromal cells, macrophages and uterine NK cells. For example, interstitial trophoblasts expressing polymorphic human leukocyte antigen-C interact with uterine NK cells through binding to their killer immunoglobulin-like receptors which likely plays a role in trophoblast invasion and reproductive success of pregnancy. Both extravillous trophoblast subtypes are critically involved in the vascular transformation of the spiral arteries into dilated conduits ensuring appropriate blood flow into the intervillous space. Failures in this remodeling process are thought to be associated with severe forms of fetal growth restriction, preeclampsia and other pregnancy complications warranting studies on the molecular regulation of extravillous trophoblast differentiation. Moreover, interstitial trophoblast-derived hormones may regulate diverse biological functions in the decidua. In particular, human chorionic gonadotrophin has been shown to promote angiogenesis and to suppress apoptosis of endometrial stromal cells. In return, decidual cells produce a plethora of soluble factors controlling trophoblast invasion in a time- and distance-dependent manner. However, the underlying mechanisms have not been fully elucidated. Here, we will summarize autocrine as well as paracrine factors regulating invasion of extravillous trophoblasts and discuss critical signaling cascades involved. In addition, we will focus on key regulatory transcription factors controlling cell column proliferation and differentiation of the human extravillous trophoblast.

Fig. 1

Development of different extravillous trophoblast subtypes and their functions. Progenitors residing at the basement membrane of cell columns (cell column trophoblast, CCT) give rise to interstitial cytotrophoblasts (iCTB) invading the uterine decidua and endovascular cytotrophoblasts (eCTB) migrating into the maternal spiral arteries.

Fig. 2

The influence of decidual cell types on interstitial trophoblast invasion and migration. Predominant cell types of the maternal decidua, uterine natural killer (uNK) cells, decidual stromal cells (DSC) and decidual macrophages produce soluble factors promoting and inhibiting trophoblast motility.

Fig. 3

Autocrine factors secreted from EVT promoting and inhibiting trophoblast motility.

Fig. 4

Signaling pathways promoting trophoblast invasion and migration. Numerous soluble growth factors expressed at the fetal-maternal interface signal through receptor tyrosine kinases (RTK) and G-protein-coupled receptors (GPCR) to provoke activation of MEK/ERK, PI3K/AKT/mTOR and Rho/ROCK signaling. Besides the JAK/STAT pathway downstream of cytokine receptor family 1 (CRF1), Wnt-dependent activation of frizzled (Fzd) receptors as well as Notch activation could be involved in controlling trophoblast motility.

Fig. 5

Expression patterns and roles of regulatory transcription factors in EVT differentiation. Cell column trophoblasts (CCT) and extravillous trophoblasts (EVT) produce activators as well as inhibitors of trophoblast proliferation and invasion. Factors such as GCM1 and TCF-4 are absent from CCT progenitors and proliferative CCTs, respectively, corroborating their positive functions in EVT differentiation and invasion.

Fig. 6

Open questions concerning regulatory mechanisms controlling human EVT differentiation and invasion. References indicate additional review articles and original publications where the respective research problem has been brought up, discussed or recently tackled.