Human placenta and trophoblast development: key molecular mechanisms and model systems

Abstract

Abnormal placentation is considered as an underlying cause of various pregnancy complications such as miscarriage, pre eclampsia and intrauterine growth restriction, the latter increasing the risk for the development of severe disorders in later life such as cardiovascular disease and type 2 diabetes. Despite their importance, the molecular mechanisms governing human placental formation and trophoblast cell lineage specification and differentiation have been poorly unravelled, mostly due to the lack of appropriate cellular model systems. However, over the past few years major progress has been made by establishing selfrenewing human trophoblast stem cells and 3dimensional organoids from human blastocysts and early placental tissues opening the path for detailed molecular investigations. Herein, we summarize the present knowledge about human placental development, its stem cells, progenitors and differentiated cell types in the trophoblast epithelium and the villous core. Anatomy of the early placenta, current model systems, and critical key regulatory factors and signalling cascades governing placentation will be elucidated. In this context, we will discuss the role of the developmental pathways Wingless and Notch, controlling trophoblast stemness/differentiation and formation of invasive trophoblast progenitors, respectively.

Derivation of macaque trophoblast stem cells

“…An alternative approach to obtaining trophoblast cell lines has been to isolate primary trophoblasts from early first trimester placental tissue 22 . It is postulated that a TSC niche resides in the early human first trimester placenta 8,[22][23][24] , where these cells are a proliferative, less differentiated progenitor cell population that gives rise to both villous cytotrophoblasts that fuse to form the syncytia as well as extravillous trophoblast (EVT) progenitor cells at the cell column tips 25 .…”

Atypical Protein Kinase C iota (PKCλ/ι) Ensures Mammalian Development by Establishing the Maternal-Fetal Exchange Interface

“…In contrast to mouse, the earliest stage of human placentation is associated with the formation of a zone of invasive primitive syncytium at the blastocyst implantation site (Boss, Chamley, & James, 2018;James, Carter, & Chamley, 2012;Knofler et al, 2019). Later, columns of CTB progenitors penetrate the primitive syncytium to form primary villi.…”

“…Later, columns of CTB progenitors penetrate the primitive syncytium to form primary villi. With the progression of pregnancy, primary villi eventually branch and mature to form the villous placenta, containing two types of matured villi; (i) anchoring villi, which anchor to maternal tissue and (ii) floating villi, which float in the maternal blood of the intervillous space (Boss et al, 2018;James et al, 2012;Knofler et al, 2019). The proliferating CTBs within anchoring and floating villi adapt distinct differentiation fates during placentation (Haider et al, 2016).…”

Placenta-Specific Genes, Their Regulation During Villous Trophoblast Differentiation and Dysregulation in Preterm Preeclampsia

“…An earlier microarray study on in vitro differentiating cytotrophoblasts identified expression changes of genes and gene clusters related to structural and functional differentiation of cytotrophoblasts [5,6]. Functional experiments utilizing cytotrophoblasts isolated from healthy term placentas found that the reprogramming of the villous trophoblast transcriptome during differentiation and the unique transcriptomic activity of the syncytiotrophoblast [27] were partly governed by cAMP through the protein kinase A (PKA) or Epac pathways [2,[5][6][7][8][9]11,12,[28][29][30][31][32]. To some extent, the morphological (syncytialization) and biochemical differentiation of cytotrophoblasts may be separate [11,12]: Epac signaling may regulate syncytialization while both Epac and PKA signaling may be involved in biochemical differentiation [2,31,33].…”

“…Preeclampsia, a life-threatening obstetrical syndrome related to placental dysfunction [32,[57][58][59][60][61][62][63][64][65], is associated with dysregulated expression or function of many PPE proteins (e.g., CGB, LEP), transcription factors (e.g., GCM1, ESRRG), and signaling and kinase pathways (e.g., ERK1/2, p38), especially when it develops preterm [19,57,[66][67][68][69][70][71][72][73][74][75]. Based on the observations that the volume [76] and cellular architecture [67][68][69][77][78][79] of villous trophoblasts are severely impacted in preterm preeclampsia, it has been proposed that either the entire cytotrophoblast differentiation program [80], or particularly syncytialization [81][82][83][84][85][86][87], are affected in preterm preeclampsia, although neither have been proven at the systems level yet.…”