# Engineering a Microphysiological System to Model the Infarct Border Zone and Interrogate Oxygen-Dependent Cell-Cell Communication in the Myocardium

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $407,153

## Abstract

PROJECT SUMMARY/ABSTRACT
 Myocardial infarction (MI) is one of the most common forms of cardiac injury. In a MI, coronary artery
occlusion leads to a local restriction of blood and oxygen supply to the myocardium, causing many immediate
and long-term changes throughout the myocardium that often manifest as arrhythmias or heart failure. Thus, a
more detailed understanding of the remodeling processes that occur both local and distant to hypoxic injury are
critically needed to develop new therapies for mitigating the progression to heart failure after MI. Recent
studies have shown that hypoxia alters the cargo found in exosomes secreted by both cardiac fibroblasts and
myocytes. This suggests that hypoxic and normoxic cardiac cell types could communicate via exosomes in
post-MI myocardium. However, the effects of exosomes secreted by hypoxic cardiac cells on normoxic cardiac
cells (and vice versa) is poorly characterized, in large part due to a lack of experimental tools. For example, the
state-of-the-art for investigating hypoxia in vitro is to modulate oxygen globally with an incubator or hypoxia
chamber. This approach does not mimic the oxygen gradients that are characteristic of post-MI myocardium
and therefore precludes the investigation of ongoing cell-cell communication between normoxic and hypoxic
cells, which could be a key mechanism of myocardial remodeling post-MI. We hypothesize that localized
hypoxia affects the phenotypes of cardiac cells locally due to the direct effects of oxygen, and distally due to
cell-cell communication between hypoxic and normoxic cells, mediated primarily by exosomes. To test this
hypothesis, we will first fabricate a new microphysiological system that: (1) implements microfluidic gas supply
channels to generate oxygen gradients; (2) has modular cell culture chambers to regulate cell-cell contact and
paracrine signaling; and (3) integrates assays for quantifying cardiac fibroblast and myocyte structural and
functional phenotypes, including existing “Heart on a Chip” contractility assays previously advanced by the PI.
We will then implement these devices for three Aims. In Aim 1, we will measure how oxygen gradients affect
cardiac fibroblast phenotype, exosome RNA and protein cargo, and the activity of the oxygen-sensitive
transcription factors, HIF-1 and HIF-2. In Aim 2, we will perform similar studies with cardiac myocytes and
quantify functional phenotypes by integrating our “Heart on a Chip” assays for measuring propagation velocity
and contractile stress. In Aim 3, we will characterize cross-talk between hypoxic fibroblasts and normoxic
cardiac myocytes, as well as hypoxic cardiac myocytes and normoxic fibroblasts. Together, our innovative
microphysiological systems and rigorous experimental approaches will reveal significant new insights into the
effects of localized hypoxic injury on the phenotypes of cardiac cell types, relevant to understanding myocardial
remodeling post-MI. Our data will also establish ...

## Key facts

- **NIH application ID:** 10817166
- **Project number:** 5R01HL153286-05
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Megan Laura McCain
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $407,153
- **Award type:** 5
- **Project period:** 2020-06-15 → 2025-08-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10817166

## Citation

> US National Institutes of Health, RePORTER application 10817166, Engineering a Microphysiological System to Model the Infarct Border Zone and Interrogate Oxygen-Dependent Cell-Cell Communication in the Myocardium (5R01HL153286-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10817166. Licensed CC0.

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