# Engineering Fetal Cell Exosomes to contain HMGB1: Its trafficking and role as an inflammatory activator in uterine cells

> **NIH NIH R21** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2020 · $145,500

## Abstract

ABSTRACT
Feto-maternal paracrine signaling, an inflammatory process, is one of the key initiators of parturition. Recently
we reported that senescent fetal tissues at term, specifically fetal membrane cells, generate damage-
associated molecular pattern markers (DAMPs) with proinflammatory properties, locally and at distant sites.
DAMPs, along with other inflammatory cytokines and chemokines, enhance the inflammatory load to transition
quiescent uterine tissues to an active state for parturition. DAMPs can reach distant sites through exosomes
(30–150-nm extracellular vesicles) released by senescent fetal cells and cause inflammatory changes by
increasing cytokine and chemokine productions in the recipient cells. One of the well-studied DAMPs in term
and preterm parturition is high-mobility group box (HMGB)1 protein. HMGB1 is a non-histone nuclear protein,
released to the cytoplasm because of nuclear injury due to cellular senescence or other insults. Senescence of
fetal amnion epithelial cells (AEC) leads to packaging of HMGB1 in exosomes. HMGB1 concentration is higher
in senescent-cell-derived exosomes, which led us to hypothesize that AEC exosomes containing HMGB1 can
either systemically or by traversing through tissues reach maternal uterine cells (decidua and myometrium),
cause functional changes by enhancing their inflammatory load (NF-kB activation and increased production of
cytokines), and contribute to the parturition process. Current studies have not been able to elucidate the
functional capabilities of exosome-encapsulated HMGB1 because senescent AEC exosomes traffic contents
other than HMGB1. To get a precise functional property of HMGB1 in exosomes, we plan to engineer
exosomes to contain a novel protein via the Exosomes for Protein Loading Via Optically Reversible Protein-
Protein Interactions (EXPLORs) method. This method is developed to overcome the limitations of conventional
exosome-based protein delivery. Using these HMGB1-encapsulated exosomes, we will test HMGB1's
functional role in vitro in decidual and myometrial cell cultures and in animal models of pregnancy. Our aims
will be
Specific Aim #1: to engineer AEC-derived exosomes to specifically contain HMGB1 by integrating a reversible
protein-protein interaction module controlled by blue light with the endogenous process of exosome
biogenesis.
Specific Aim #2: to test the functional role of HMGB1-rich AEC-derived exosomes in in vitro and pregnant
animal models.
We expect to generate exosomes containing specific cargo and test its functional role in promoting
inflammation and parturition. Successful generation of exosomes loaded with specific cargo will introduce a
new technology to load exosomes with functionally viable proteins. Future studies will test the usefulness of
exosomes with therapeutic proteins that can be used for interventional purposes in adverse pregnancies.

## Key facts

- **NIH application ID:** 9883717
- **Project number:** 5R21AI140249-02
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** RAMKUMAR MENON
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $145,500
- **Award type:** 5
- **Project period:** 2019-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9883717

## Citation

> US National Institutes of Health, RePORTER application 9883717, Engineering Fetal Cell Exosomes to contain HMGB1: Its trafficking and role as an inflammatory activator in uterine cells (5R21AI140249-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9883717. Licensed CC0.

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