# Placental Organoids to Model Preeclampsia

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2024 · $417,500

## Abstract

While the underlying etiology of preeclampsia (a hypertensive disorder of pregnancy) is not
known, the disease starts with shallow placentation and placental ischemia which in turn releases
excess of anti-angiogenic proteins such as soluble fms-like tyrosine kinase 1 (sFLT1) in the mother's
bloodstream that is responsible for the systemic maternal endothelial dysfunction. Self-renewing
three-dimensional epithelial organoids that closely resemble the structure and physiology of the
original organ have been successfully developed into various tissue types using human induced
pluripotent stem cells (hiPSCs). However, organoids of the human placental trophoblasts using
hiPSCs are yet to be generated. Our goal of this proposal is to generate trophoblast organoids
from disease-specific hiPSCs to study preeclampsia pathogenesis and to screen for drugs as
potential treatment targets. We will generate a new model of trophoblast organoid using hiPSCs,
replicating the early stage of gestation from normal and preeclamptic pregnancies, a time in
development that has – until now – has been mostly inaccessible to researchers. In aim 1, we will
optimize trophoblast organoid protocols in our laboratory using hiPSCs derived trophoblast
differentiation method from donor fibroblasts and will confirm that these organoids phenotypically and
functionally behave like first trimester villous tissue. We will then test the hypothesis that the functional
capacity of trophoblast organoids derived from hiPSCs obtained from early-onset preeclampsia will be
impaired when compared to trophoblast organoids derived from non-hypertensive controls. In aim 2,
we will model maternal syndrome of preeclampsia in nude mice with factors made by human placenta.
To model human preeclampsia, we will generate trophoblast organoids using hiPSCs derived from
placental fibroblasts from women carrying a fetus with trisomy 13, a disorder characterized by 10-fold
excess risk of preeclampsia due to extra copy of sFLT1 gene on chromosome 13. We will then test in
vivo efficacy of monoclonal antibodies that target the unique C-terminus of human sFLT1-i14 (the
isoform that is primate-specific) for enhanced clearance of sFLT1 from systemic circulation. Due to the
organoid's ready access and ability to replicate the early stages of development from well-
characterized cells, the trophoblast organoid model promises to significantly improve our
understanding of preeclampsia and provides rapid screening methods for testing potential drugs
and furthering precision medicine methods in obstetrics. Our studies will have major implications
not only for the pathogenesis of preeclampsia, but also for short and long-term cardiovascular
complication in these women.

## Key facts

- **NIH application ID:** 10748388
- **Project number:** 5R01HL167268-02
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** S. Ananth Karumanchi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $417,500
- **Award type:** 5
- **Project period:** 2022-12-15 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10748388

## Citation

> US National Institutes of Health, RePORTER application 10748388, Placental Organoids to Model Preeclampsia (5R01HL167268-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10748388. Licensed CC0.

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