# Cell Therapy for Neuroprotection in Congenital Heart Disease

> **NIH NIH R01** · CHILDREN'S RESEARCH INSTITUTE · 2024 · $811,488

## Abstract

PROJECT SUMMARY
Significant neurological delay is emerging as one the most important current challenges for children with
congenital heart disease (CHD), yet few treatment options are currently available. In our first period of funding,
we proposed the use of cardiopulmonary bypass (CPB) as a cell delivery system in infants with CHD as a novel
approach for improving the neurological impairments in CHD. Our published and unpublished work has
demonstrated the efficacy and utility of this approach, determining the systemic effects of delivery bone marrow-
derived mesenchymal stromal cell (BM-MSC) via CPB and the effect on white matter (WM) and sub-ventricular
zone (SVZ) development. Most notably, the first award successfully led to development of a phase 1 clinical trial
termed “MeDCaP” at Children’s National. Using our translational piglet model, we have demonstrated cellular,
structural, and behavioral improvements after BM-MSC delivery through CPB and generated critical information
for bench-to-bedside translation. However, the mechanisms underlying the therapeutic action of BM-MSCs still
remain largely unknown. This R01 renewal will address the key knowledge gaps with the goal of further
enhancing our cell-based treatment for neuroprotection in the CHD population. Exosome is a class of
extracellular vesicles loaded with bioactive molecules such as microRNA (miRNA). Exosomes derived from BM-
MSCs (BM-MSCexo) can play a major role in the effects on surrounding cells and tissues and elicit favorable
responses in various diseases. We have established a pipeline for post-cell delivery integrated transcriptomic
analysis of exosomal miRNAs from BM-MSCs and host tissue mRNA. Our preliminary studies have identified
the BM-MSCexo-derived miRNAs as putative key drivers of reduced neuronal apoptosis and microglial activation
observed after BM-MSC treatment in the cerebral cortex. The overarching goal of this renewal proposal is to
establish detailed molecular signatures from critical cell populations for tissue repair and regeneration at single
cell resolution after BM-MSC delivery; we will then use those molecular signatures as roadmaps to identify novel
molecular entities within the BM-MSCexo that account for the disease-modifying bioactivity in tissue injury after
pediatric cardiac surgery. The renewal studies will test our central hypothesis that specific exosomal cargo
constituents from BM-MSCs promote repair and regenerative processes both through neural progenitors and
regulatory T cells, thereby improving neurological outcomes and post-operative course. To retroactively identify
key exosomal bioactive molecules, we will determine the transcriptional and chromatin landscape of three
specific cell populations: 1) SVZ neural stem and progenitor cells; 2) WM oligodendrocytes; and 3) regulatory T
cells. Together with our ongoing clinical trial established based on the previous award, identifying molecular
signatures of BM-MSC treatment and mining specifi...

## Key facts

- **NIH application ID:** 10850659
- **Project number:** 5R01HL139712-06
- **Recipient organization:** CHILDREN'S RESEARCH INSTITUTE
- **Principal Investigator:** Nobuyuki Ishibashi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $811,488
- **Award type:** 5
- **Project period:** 2017-12-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10850659

## Citation

> US National Institutes of Health, RePORTER application 10850659, Cell Therapy for Neuroprotection in Congenital Heart Disease (5R01HL139712-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10850659. Licensed CC0.

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