# Cell Therapy for Neuroprotection in Congenital Heart Disease

> **NIH NIH R01** · CHILDREN'S RESEARCH INSTITUTE · 2021 · $645,834

## Abstract

PROJECT SUMMARY/ABSTRACT
Significant neurodevelopmental delay is emerging as one the most important current challenges for patients
with congenital heart disease (CHD). Clinical studies demonstrate that reduced oxygen delivery due to CHD in
utero results in subnormal brain development. Newly-developed brain injury after cardiac surgery is also
common in neonates whose brains are already dysmature at the time of surgery. However no treatment
options are currently available for brain damage in children with CHD.
Our series of studies show that potential cell-based interventions for improvement of CHD-induced brain
damage include: 1) promoting white matter (WM) regeneration through endogenous oligodendrocyte
progenitors; 2) restoring the neurogenic potential of subventricular zone (SVZ) neural stem/progenitor cells;
and 3) controlling prolonged microglia activation after cardiopulmonary bypass (CPB)-induced insults.
Mesenchymal stromal cells (MSCs) are multipotent, nonhematopoietic cells that possess both
immunomodulatory and regenerative properties, and can treat a wide range of diseases including hypoxic
brain injury. Various rodent studies have shown that in the brain MSCs: 1) accelerate WM remyelination
through the activation of endogenous oligodendrocyte progenitors; 2) promote neurogenesis from SVZ neural
stem/progenitor cells; and 3) regulate microglia activation after hypoxic-ischemic brain insults. Multiple clinical
trials have also established the safety of MSC-based therapy. These findings have led to our principal
hypothesis that: MSC delivery to the early postnatal brain promotes endogenous regeneration of
damaged neuronal and glia cells in children with CHD. Pediatric cardiac surgery provides a unique
opportunity to control cerebral perfusion of the developing brain though CPB. We are proposing the use of
CPB itself as a new MSC delivery system in the CHD population.
The proposed project will test the following specific related hypotheses: 1) MSCs govern CPB-induced
systemic inflammation and reduce microglia activation in the brain (Aim 1); 2) MSC delivery accelerates WM
regeneration through activation of endogenous oligodendrocyte progenitors (Aim 2); 3) MSC treatment
promotes cortical regeneration through activation of endogenous SVZ neural stem/progenitor cells (Aim 3).
Using our unique porcine hypoxia and CPB model, we will determine: 1) the systemic effect of MSC delivery
through CPB during CHD surgery (Aim 1); 2) the effect of MSC treatment on WM oligodendrocyte progenitors
(Aim 2); and 3) the effect of MSC treatment on SVZ neural stem/progenitor cells (Aim 3).
The goal of the project is to design novel cell-based therapies aimed at regenerating damaged neural and glial
cells, and improving neurodevelopment in children with CHD. Since the cellular/anatomical structure and
developmental process of the piglet brain closely resemble their human counterpart, the results will also assist
in providing new regenerative approaches to a w...

## Key facts

- **NIH application ID:** 10075303
- **Project number:** 5R01HL139712-04
- **Recipient organization:** CHILDREN'S RESEARCH INSTITUTE
- **Principal Investigator:** Nobuyuki Ishibashi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $645,834
- **Award type:** 5
- **Project period:** 2017-12-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10075303

## Citation

> US National Institutes of Health, RePORTER application 10075303, Cell Therapy for Neuroprotection in Congenital Heart Disease (5R01HL139712-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10075303. Licensed CC0.

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