Abstract
Exposure to toxic heavy metals contributes to the development of pregnancy complications that can adversely affect fetal development. Despite increasing evidence suggesting the negative health impact of heavy metals, investigating their adverse effects in the context of human pregnancy remains a major challenge due to the difficulty of human subject research and the limited capacity of animal models to properly represent the anatomy and function of the human reproductive system. Motivated by problem, here we describe a microengineered in vitro model designed to reverse engineer the maternal-fetal interface in the human placenta. This biomimetic system enables advanced capabilities to grow human trophoblast cells and fetal vascular endothelial cells in a physiological spatial arrangement and dynamic culture conditions to engineer the placental barrier in vitro that can emulate regulated material transport between maternal and fetal circulations. Using cadmium (CdCl2 ) as a representative example of heavy metals, we investigate whether and how this environmental chemical affects the human placental barrier and its physiological function as a gatekeeper. Our study also examines the role of membrane transporters in the maternal-to-fetal transfer of cadmium to provide insights into efflux transporter-medicated protection against environmental exposures during pregnancy.We used soft lithography to construct a compartmentalized elastomeric device consisting of two overlapping chambers separated by a thin semipermeable membrane. After sterilization and surface coating with extracellular matrix protein, the device was seeded with BeWo b30 human trophoblast cells and primary human villous endothelial cells on the opposite sides of the membrane. The bi-layer tissue was then cultured under perfusion conditions by using syringe pumps connected to each chamber. To mimic the physiological process of placental development, we treated the trophoblast cell layer in the maternal chamber with forskolin (50 µM) to induce syncytialization.Our microengineered model of the human placental barrier formed a tight barrier (evaluated by expression of E-cadherin and VE-cadherin), secreted the pregnancy hormone human chorionic gonadotropin beta (hCGβ), and supported physiological maternal-to-fetal transport of glucose. Following CdCl2 treatment (0.5-50 µM), we observed concentration-dependent deleterious responses of the maternal and fetal tissues as demonstrated by reduced cell viability and placental hormone secretion, compromised barrier function, and increased secretion of proinflammatory cytokines. The results also indicated upregulated expression of metallothioneins IA and IIA (MT-IA/IIA) metal binding proteins.The placenta-on-a-chip is an innovative and translational in vitro platform for the study of environmental chemical toxicity in the human placenta. With further improvements, this technology may advance our ability to model, interrogate, and predict the potential of xenobiotics to disrupt placentation and maintenance of human pregnancy.
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