Animal models of the placenta accreta spectrum: current status and further perspectives

Abstract

Placenta accreta spectrum disorder (PAS) is a kind of disease of placentation defined as abnormal trophoblast invasion of part or all of the placenta into the myometrium, even penetrating the uterus. Decidual deficiency, abnormal vascular remodeling in the maternal-fetal interface, and excessive invasion by extravillous trophoblast (EVT) cells contribute to its onset. However, the mechanisms and signaling pathways underlying such phenotypes are not fully understood, partly due to the lack of suitable experimental animal models. Appropriate animal models will facilitate the comprehensive and systematic elucidation of the pathogenesis of PAS. Due to the remarkably similar functional placental villous units and hemochorial placentation to humans, the current animal models of PAS are based on mice. There are various mouse models induced by uterine surgery to simulate different phenotypes of PAS, such as excessive invasion of EVT or immune disturbance at the maternal-fetal interface, which could define the pathological mechanism of PAS from the perspective of the "soil." Additionally, genetically modified mouse models could be used to study PAS, which is helpful to exploring the pathogenesis of PAS from the perspectives of both "soil" and "seed," respectively. This review details early placental development in mice, with a focus on the approaches of PAS modeling. Additionally, the strengths, limitations and the applicability of each strategy and further perspectives are summarized to provide the theoretical foundation for researchers to select appropriate animal models for various research purposes. This will help better determine the pathogenesis of PAS and even promote possible therapy.

Keywords: animal model; decidual deficiency; mouse placenta; placenta accreta spectrum; placenta development; trophoblast invasion.

Figure 1

Morphology of mouse (left) and human (right) placenta. Left: Three layers clearly in the mouse placenta. The upper is maternal decidua. The middle layer of the supportive JZ contains spongiotrophoblasts, which give rise to TGCs and glycogen trophoblast cells. Both TGCs and glycogen trophoblast cells are invasive. The labyrinth is the functional structure of the mouse placenta where gas/nutrient exchange occurs. Maternal blood is separated from fetal blood by SynT-I, SynT-II, and sinusoidal giant cells. Right: The functional structure for gas/nutrient exchange is the chorionic villus in the human placenta. EVTs arise from the trophoblast cell column and are highly invasive, penetrating up to one-third of the thickness of the uterus. Endovascular EVTs extensively remodel maternal spiral arterioles to ensure correct blood supply to the growing embryo. Trophoblast giant cells (TGCs), junctional zone (JZ), extravillous trophoblast cells (EVTs), syncytiotrophoblast-I (SynT-I), syncytiotrophoblast- II (SynT-II). Modified from (20).

Figure 2

Major event time points in mouse and human pregnancy. The timeline for both species is calculated from conception. Days of development are denoted embryonic (E) in the mouse and week (Wk) or day (D) of development in the human. Late blastocyst implantation in mice occurred at approximately E4.5, followed by endometrial decidualization. The formation of the labyrinth at approximately E8.5, with branching morphogenesis complete by E10.5. At E10.5, the junctional zone and TGCs are also fully formed, and glycogen trophoblast cells continue to differentiate and invade the uterus along with specific TGC subtypes and form a fully functional placenta. At the same time, the embryo developed rapidly at the later stage until delivery at approximately E19.5. In humans, after a series of processes, such as trophoblast cell invasion and uterine spiral artery remodeling, a mature placenta is formed at approximately 12 weeks of gestation. The fetus develops rapidly in the later stage and is normally delivered at approximately 37–40 weeks.