A microphysiological model of human trophoblast invasion during implantation

Ju Young Park, Sneha Mani, Geremy Clair, Heather M. Olson, Vanessa L. Paurus, Charles K. Ansong, Cassidy Blundell, Rachel Young, Jessica Kanter, Scott Gordon, Alex Y. Yi, Monica Mainigi () and Dan Dongeun Huh ()
Additional contact information
Ju Young Park: University of Pennsylvania
Sneha Mani: Division of Reproductive Endocrinology and Infertility, University of Pennsylvania Perelman School of Medicine
Geremy Clair: Biological Sciences Division, Pacific Northwest National Laboratory
Heather M. Olson: Biological Sciences Division, Pacific Northwest National Laboratory
Vanessa L. Paurus: Biological Sciences Division, Pacific Northwest National Laboratory
Charles K. Ansong: Biological Sciences Division, Pacific Northwest National Laboratory
Cassidy Blundell: University of Pennsylvania
Rachel Young: University of Pennsylvania
Jessica Kanter: Division of Reproductive Endocrinology and Infertility, University of Pennsylvania Perelman School of Medicine
Scott Gordon: Children’s Hospital of Philadelphia
Alex Y. Yi: University of Pennsylvania
Monica Mainigi: Division of Reproductive Endocrinology and Infertility, University of Pennsylvania Perelman School of Medicine
Dan Dongeun Huh: University of Pennsylvania

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Successful establishment of pregnancy requires adhesion of an embryo to the endometrium and subsequent invasion into the maternal tissue. Abnormalities in this critical process of implantation and placentation lead to many pregnancy complications. Here we present a microenigneered system to model a complex sequence of orchestrated multicellular events that plays an essential role in early pregnancy. Our implantation-on-a-chip is capable of reconstructing the three-dimensional structural organization of the maternal-fetal interface to model the invasion of specialized fetal extravillous trophoblasts into the maternal uterus. Using primary human cells isolated from clinical specimens, we demonstrate in vivo-like directional migration of extravillous trophoblasts towards a microengineered maternal vessel and their interactions with the endothelium necessary for vascular remodeling. Through parametric variation of the cellular microenvironment and proteomic analysis of microengineered tissues, we show the important role of decidualized stromal cells as a regulator of extravillous trophoblast migration. Furthermore, our study reveals previously unknown effects of pre-implantation maternal immune cells on extravillous trophoblast invasion. This work represents a significant advance in our ability to model early human pregnancy, and may enable the development of advanced in vitro platforms for basic and clinical research of human reproduction.

Date: 2022
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DOI: 10.1038/s41467-022-28663-4

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