# Modeling normal and abnormal trophoblasts

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2021 · $358,551

## Abstract

PROJECT SUMMARY
Very little is known of human placental development in the period between one and five weeks of gestation
when trophoblasts invade the uterus, form the primitive syncytium and cytotrophoblast, and then primary villi.
Thus, models are needed to study the molecular and cellular mechanisms controlling early human placental
development and what can go wrong with these processes to cause placental disease and early conceptus
loss. It is now well established that human embryonic stem cells (ESC) and induced pluripotent stem cells
(iPSC) can be driven along the trophoblast lineage by exposing them to BMP4 and inhibiting the signaling
pathways that maintain the pluripotent phenotype. The overall premise is that this in vitro system is a valuable
model for mimicking placental trophoblast formed early in the first trimester of pregnancy when it is most
vulnerable to many of the same hazards that threaten an in vivo pregnancy early in its existence. The project
will use this stem cell model of early trophoblast development to understand the development of the placenta in
the earliest stages of pregnancy and the immediate pathological basis of early onset preeclampsia (EOPE), a
disease linked to shallow placentation and insufficient perfusion with maternal blood. There are three aims:
1) Test the hypothesis that villous TB from the first half of the first trimester represents a transitional state
between the primitive placenta encountered at implantation and the mature placenta of the second and third
trimester. The goal is to validate the notion that the “primitive” TB generated from ESC and iPSC is an in vitro
equivalent of early placental TB. Experiments will also confirm preliminary observations that first trimester
villous TB shares many features of its molecular signature with both this primitive TB derived from pluripotent
cells and more mature placental TB from the second and third trimesters. 2) Employ the stem cell model of
trophoblast differentiation to test the hypothesis that stress response pathways are already aberrant in EOPE
placentas upon initial formation of trophoblast. The goal is to employ RNAseq analysis and DNA methylation
profiling to compare gene and gene network changes associated with PE and CTL cells when they are cultured
under normal and stressful oxygen conditions. 3) Test the hypothesis that a better representation of
trophoblast emergence will be gained by conducting the differentiation of the pluripotent stem cells to
trophoblast with cultured spheroids rather than in 2D-cultures. The plan is to use such a system to follow the
emergence of villous trophoblast within organoids. Additionally, trophoblast stem cells (TSC) will be generated
from ESC and iPSC and also use these along with ESC/iPSC to create chimeric organoids. Finally the fate of
these organoids will be examined when they are placed under the mammary fat pads and kidney capsules of
immunocompromised mice to determine whether they exhibit physiolo...

## Key facts

- **NIH application ID:** 10188575
- **Project number:** 5R01HD094937-04
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** Toshihiko Ezashi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $358,551
- **Award type:** 5
- **Project period:** 2018-09-25 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10188575

## Citation

> US National Institutes of Health, RePORTER application 10188575, Modeling normal and abnormal trophoblasts (5R01HD094937-04). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10188575. Licensed CC0.

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