PNNL

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 (EVTs) into the maternal uterus. Using primary human cells isolated from clinical specimens, we demonstrate in vivo-like directional migration of EVTs towards a microengineered maternal vessel and their interactions with the endothelium necessary for vascular remodeling. Through parametric variation of the cellular microenviroment and proteomic analysis of microenigneered tissues, we show the important role of decidualized stromal cells as a regulator of EVT migration. Furthermore, our study reveals previously unknown effects of pre-implantation maternal immune cells on EVT 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.