Biomimetic Placenta-Fetus Model Demonstrating Maternal–Fetal Transmission and Fetal Neural Toxicity of Zika Virus

Abstract

Recent global epidemics of viral infection such as Zika virus (ZIKV) and associated birth defects from maternal-fetal viral transmission highlights the critical unmet need for experimental models that adequately recapitulates the biology of the human maternal-fetal interface and downstream fetal development. Herein, we report an in vitro biomimetic placenta-fetus model of the maternal-fetal interface and downstream fetal cells. Using a tissue engineering approach, we built a 3D model incorporating placental trophoblast and endothelial cells into an extracellular matrix environment and validated formation of the maternal-fetal interface. We utilized this model to study ZIKV exposure to the placenta and neural progenitor cells. Our results indicated ZIKV infects both trophoblast and endothelial cells, leading to a higher viral load exposed to fetal cells downstream of the barrier. Viral inhibition by chloroquine reduced the amount of virus both in the placenta and transmitted to fetal cells. A sustained downstream neural cell viability in contrast to significantly reduced viability in an acellular model indicates that the placenta sequesters ZIKV consistent with clinical observations. These findings suggest that the placenta can modulate ZIKV exposure-induced fetal damage. Moreover, such tissue models can enable rigorous assessment of potential therapeutics for maternal-fetal medicine.

Inspired by the human placenta: a novel 3D bioprinted membrane system to create barrier models

“…Thus, fibroblasts seem to impact barrier formation. Comparing TEER values to the literature, BeWo culture on the biological membrane reached similar levels (about ) as on PET filter membrane coated with collagen or with polymerized GelMA 7 , 41 . The coculture of BeWo and fibroblasts on the biological membrane system, on the contrary to monotypic BeWo culture, reached more than twice the TEER values ( ), but were still below levels reported for single BeWo culture on PET membranes (pore sizes of 1– m) coated with Matrigel or collagen IV (about 1200 and 600 respectively) 5 , 6 .…”

“…Gelatine is a commonly used ECM component in cell culture and its derivative GelMA is well characterized and widely used in 3D bioprinting, which Yue et al reviewed comprehensively 36 . Many cell types of different tissue origin have been cultured successfully on GelMA: endothelial (HUVEC 37 , 38 , ECFC 39 ) and epithelial cells (Ishikawa 40 , BeWo 41 ) as well as cells of mesenchymal origin (NIH-3T3 42 , MG63, osteoblasts 43 ).…”

A Gelatin Hydrogel to Study Endometrial Angiogenesis and Trophoblast Invasion

“…We expect that monolayer formation is dependent on initial cell seeding density, attachment time, and time in culture. Future in-depth characterization of epithelial monolayers include immunostaining for characteristic markers of epithelial sheets, including E-cadherin and cytokeratin 18, and detailed studies of monolayer functionality, including transepithelial electrical resistance measurements [35,53,54].…”

Late Neurological Consequences of Zika Virus Infection: Risk Factors and Pharmaceutical Approaches

“…Concerning the development of CZS, it can also be speculated that a pregnant woman’s individual response to infection influences the efficiency with which ZIKV crosses the placental barrier. Trophoblasts, placental barrier cells, are permissive to ZIKV only during a narrow time-frame, likely in the first trimester of gestation [48,53,68,69,70]. This is probably one of the reasons why infection during this stage of pregnancy is usually associated to the birth of babies with more severe neurological outcomes.…”