# Microphysiological Model of Human Cardiac Sympathetic Innervation

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $74,154

## Abstract

PROJECT SUMMARY
Goal: We will develop and validate a microphysiological platform of human cardiac sympathetic innervation for
in vitro modeling of the human cardiac sympathetic innervation and apply autonomic neuron specification and
its interaction with a fatal cardiac disease. The heart is heavily innervated by the autonomic nervous system that
consists of both parasympathetic and sympathetic nerves, providing feedback control and regulate overall
cardiac performance. Historically, the development of new therapeutic agents targeting cardiac neuropathies
have utilized animal models, which exhibited various limitations due to the disparity in homeostatic mechanisms
of autonomic nervous systems and the inability to recapitulate accurate human disease phenotypes. In our
proposed work, we will develop a novel compartmentalized 3D microelectrode array (MEA) co-culture platform
to model human sympathetic innervation and address the fundamental questions on sympatho-cardiac
connections, reciprocal regulation, and development of cardiac and autonomic cells. Furthermore, with
arrhythmogenic cardiomyopathy (ACM) patient-derived human induced pluripotent stem cells (hiPSC), we
expect to recapitulate ACM syndromic phenotypes and examine the diseased cardiac sympathetic innervation
on our microphysiological platform, conducive to understanding neuromodulation as well as the neuronal
contribution to heart function and disease. We will leverage state-of-art techniques developed by our team: (1)
high-throughput multimodal 3D microelectrode arrays, (2) single-cell transcriptomes from human autonomic
neurons and cardiac cells for a continuum of molecular changes during their interactions, (3) genetic reporter
systems with isogenic control cells to define specific human autonomic neuron populations and perform high-
resolution analysis of the neuron-cardiac connection, (4) the optogenetic control of neuronal activities on
connected cardiac tissue. Focus/Aim: Our proposed research focuses on developing an in vitro platform to
study neuro-cardiac interactions with hiPSCs. We will develop and optimize a compartmentalized 3D MEA co-
culture platform in multi-well format to monitor electrophysiology properties of cardiomyocytes, sympathetic
neurons and neuro-cardiac junction, followed by evaluation of the platform’s ability to support functional synapse
formation with optogenetic neuronal stimulation (Aim 1). We will also generate the developmental trajectory of
hiPSC-cardiomyocytes connected to hiPSC-sympathetic neurons through single cell transcriptomic analysis, as
well as structural and functional changes in hiPSC-CMs following neuronal stimulations (Aim 2). Furthermore,
we will examine whether the innervation affects cell fate choice (Aim 2). In Aim 3, we will employ ACM patient-
derived hiPSC/hESCs harboring desmosomal gene mutations onto our microphysiological platform and
investigate the role of sympathetic innervation in pathogenic phenotypes presented by ACM,...

## Key facts

- **NIH application ID:** 11126110
- **Project number:** 3R01HL164936-03S1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Deok-Ho Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $74,154
- **Award type:** 3
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11126110

## Citation

> US National Institutes of Health, RePORTER application 11126110, Microphysiological Model of Human Cardiac Sympathetic Innervation (3R01HL164936-03S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11126110. Licensed CC0.

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