Self‐assembled human placental model from trophoblast stem cells in a dynamic organ‐on‐a‐chip system

Abstract

The placental barrier plays a key role in protecting the developing fetus from xenobiotics and exchanging substances between the fetus and mother. However, the trophoblast cell lines and animal models are often inadequate to recapitulate the key architecture and functional characteristics of human placental barrier. Here, we described a biomimetic placental barrier model from human trophoblast stem cells (hTSCs) in a perfused organ chip system. The placental barrier was constructed by co‐culture of hTSCs and endothelial cells on the opposite sides of a collagen‐coated membrane on chip. hTSCs can differentiate into cytotrophoblasts (CT) and syncytiotrophoblast (ST), which self‐assembled into bilayered trophoblastic epithelium with placental microvilli‐like structure under dynamic cultures. The formed placental barrier displayed dense microvilli, higher level secretion of human chorionic gonadotropin (hCG), enhanced glucose transport activity. Moreover, RNA‐seq analysis revealed upregulated ST expression and activation of trophoblast differentiation‐related signalling pathways. These results indicated the key role of fluid flow in promoting trophoblast syncytialization and placental early development. After exposure to mono‐2‐ethylhexyl phthalate, one of the endocrine disrupting chemicals, the model showed inhibited hCG production and disturbed ST formation in trophoblastic epithelium, suggesting impaired placental structure and function elicited by environmental toxicants. Collectively, the hTSCs‐derived placental model can recapitulate placenta physiology and pathological response to external stimuli in a biomimetic manner, which is useful for the study of placental biology and associated diseases.

Directed biomechanical compressive forces enhance fusion efficiency in model placental trophoblast cultures

“…Trophoblast fusion is hence critical for a successful pregnancy as the syncytiotrophoblast regulates transport between mother and fetus, and dysregulated fusion is associated with abnormal placentation that can lead to significant obstetric complications such as preeclampsia and intrauterine growth restrictions 5 . While several models exist with which to study placental transport 6,7 including recent advanced 'on-a-chip' devices [8][9][10][11][12][13] , creating perfectly fused syncytial sheets remains challenging in culture. While novel pluripotent stem cell models do provide one avenue to enhance fusion efficiencies [14][15][16] , developing a better understanding of the fundamental factors influencing syncytialization could further improve upon these advanced models, and enhance our understanding of the factors driving disease progression during pregnancy.…”