Project Description Narrative:
The amnion is a critical component of the amniochorionic fetal membrane that encases amniotic fluid and provides immune and mechanical protection to the developing fetus. In humans, amniogenesis is triggered during implantation. In implanting blastocysts, the aggregate of pluripotent epiblast cells begins to polarize, establishing a radially organized cyst structure with a central lumen (future amniotic cavity). As implantation continues, the epiblast cells at the uterine pole begin to flatten, lose pluripotency, and take on amnion fate, while, at the other pole, columnar pluripotent epiblast cells form the embryonic disc. The result is an asymmetric cystic structure known as the amniotic sac.
While essential for continuation of pregnancy, the early events surrounding amniogenesis and amniotic sac formation have been difficult to study because of ethical considerations which limit direct experiments on human embryos, and due to differences in timing and location of amnion formation between humans and well-established animal models such as mice. Clinically, several studies have established that defects in amnion integrity (e.g., tissue microfracture) can trigger preterm rupture of the fetal membranes, a common complication that accounts for approximately 40% of spontaneous premature births—births occurring prior to gestation week 37—and contribute to an increase in infant mortality and morbidity (premature births account for approximately 10-12% of all births in the US). While data is not available, it is likely that failure to produce a functional amniotic membrane is responsible for a large number of early pregnancy complications. Importantly, according to a study in 2018, preterm births present a significant financial burden with an average cost of approximately $170,000, from birth (gestational age at birth approximately 27.5 weeks) to discharge. Infants born at 24 weeks gestation have the highest average expenses of $600,000. In Wisconsin, one in 10 babies were born preterm in 2021, which is similar to the national average (10.5%). However, the rate of preterm birth is highest among Black infants (15.6%), followed by Natives/Alaska Natives (12.7%); the remaining population (e.g., Caucasian, Asian) was below average (ranging from 8.3% to 10%). Also, preterm birthrate has been increasing in Wisconsin from 9.3% in 2011 to 10% in 2021. Particularly in urban communities such as Milwaukee County, the leading cause of infant deaths is complications caused by preterm birth (0.16% of live births in 2019), which is higher than the Wisconsin (0.12%) and national average (0.09%).
These data reveal that preterm birth severely impacts urban and minority populations in Wisconsin. Given this alarming trend that can impact Wisconsin families with significant financial burden, it is of critical importance to investigate the formation of the amnion, a critical component of the amniochorionic fetal membrane, and gain insights for developing future diagnosis and therapeutic strategies. Despite these immense health and financial implications, there is still a knowledge gap in understanding molecular processes underlying amnion development, primarily due to the lack of adequate in vitro models.
To overcome this limitation, this project’s lead researcher has recently developed and published a new human pluripotent stem cell (hPSC) based amnion system (known as Glass-3D+BMP) that allows for a robust formation of cysts uniformly composed of squamous amniotic cells (amniotic cysts). Using this model, the research team has already provided significant molecular insights into several amniogenic processes. They have uncovered two previously unrecognized key players that are involved in human amniogenesis. For this project, they will use this Glass-3D+BMP model to investigate how these key players regulate amnion formation. These studies will increase the understanding of human amniogenesis and ultimately improve the detection and treatment of amniotic membrane pathologies and related pregnancy complications.