Modelling the Human Placental Interface In Vitro-A Review

Abstract

Acting as the primary link between mother and fetus, the placenta is involved in regulating nutrient, oxygen, and waste exchange; thus, healthy placental development is crucial for a successful pregnancy. In line with the increasing demands of the fetus, the placenta evolves throughout pregnancy, making it a particularly difficult organ to study. Research into placental development and dysfunction poses a unique scientific challenge due to ethical constraints and the differences in morphology and function that exist between species. Recently, there have been increased efforts towards generating in vitro models of the human placenta. Advancements in the differentiation of human induced pluripotent stem cells (hiPSCs), microfluidics, and bioprinting have each contributed to the development of new models, which can be designed to closely match physiological in vivo conditions. By including relevant placental cell types and control over the microenvironment, these new in vitro models promise to reveal clues to the pathogenesis of placental dysfunction and facilitate drug testing across the maternal-fetal interface. In this minireview, we aim to highlight current in vitro placental models and their applications in the study of disease and discuss future avenues for these in vitro models.

Keywords: bioprinting; in vitro models; maternal-fetal interface; microfluidics; placenta; placenta-on-a-chip; trophoblast invasion.

Figure 1

Placental development timeline, trophoblast invasion, and mature placental structure. (a) Diagram of trophoblast invasion around day 9, wherein the syncytiotrophoblast layer surrounding the embryoblast begins to invade the endometrium. (b) Mature placental structure showing maternal and fetal vasculature. (c) Focus on exchange of nutrients between open maternal blood and closed fetal circulation across the two trophoblastic layers.

Figure 2

Modeling the placental barrier in vitro. (a) Diagram of transport between maternal and fetal blood supplies across the syncytiotrophoblast (SCT) and cytotrophoblast (CT). (b) A modified transwell model using a bioprinted layer of fibroblasts with trophoblasts and endothelial cells cultured on either side (based on design in [26]). (c) A transwell model with a layer of trophoblasts cultured on top of vasculature in a 3D gel matrix. Other cell types (blue) can be cultured below the transwell to test the effect of cell secretions (based on design in [27]). (d) Endothelial cells and trophoblasts can be cultured on either side of a permeable membrane in a PDMS microfluidic device with flow (based on designs in [17,28]). (e) Endothelial cells and trophoblasts may also be cultured on either side of a 2PP-fabricated membrane to achieve different geometries (based on design in [29]).

Figure 3

Summary of trophoblast invasion models. (a) Diagram of trophoblast invasion of the endometrium in vivo. (b) A transwell model with a monolayer of trophoblasts invading a gel towards the chemoattractant in the well (based on designs in [32,33,34,35]). (c) A spheroid model in a well plate with trophoblasts invading the underlying gel towards a monolayer of cells (based on design in [36]). (d) A bioprinted model consisting of concentric rings of a gel, with trophoblasts in the outermost layer and a chemoattractant in the innermost layer (based on designs in [37,38,39]). (e) A microfluidic device with trophoblasts suspended in a gel in the center channel with medium flowing through the channels on either side (based on design in [40,41]). The chemoattractant is included in only one media channel in this design.

Figure 4

Summary of important components and possible applications of in vitro placental models. Immune cells may include Hofbauer cells or macrophages. Extracellular matrix (ECM) may be composed of collagen, laminin, fibronectin, or glycoproteins. Vascularization may be achieved via patterned microvessels, sacrificial molds, or self-assembled networks. Cell sources include cell lines, primary cells, or stem cells. Different geometries may be created by using 2D artificial membranes or two-photon polymerization (2PP). Relevant mechanical cues include fluid flow, matrix stiffness, and substrate stiffness. Possible applications in basic biology include studying the mechanisms of normal and pathological placental development and function. In vitro models may also be applied to study the transport and effects of pollutants, pathogens, and drugs.