# Investigating the pathogenesis of Moyamoya Disease using patient derived induced pluripotent stem cells

> **NIH NIH R21** · STANFORD UNIVERSITY · 2022 · $196,750

## Abstract

PROJECT SUMMARY
Moyamoya Disease (MMD) is a rare, chronic cerebrovascular disease that affects the blood vessels of the brain,
causing occlusion of major cerebral arteries and formation of fragile vessels in the vicinity. Clinical manifestations
of MMD are transient ischemic attacks and cerebral infarctions, often leading to ischemic or hemorrhagic stroke.
Invasive revascularization surgery is the only current treatment available. There may be a combination of genetic,
circulating and environmental factors involved in the pathogenesis of MMD, however, the molecular mechanisms
underlying MMD is largely unknown, mainly due to the lack of established MMD-specific cellular or animal
models. In this proposal we aim to understand the pathogenesis of MMD by using MMD patient- derived iPSCs
cellular models in combination with functional assays and high throughput sequencing approaches.
The main histopathological finding in MMD is the fibro-cellular thickening of the innermost layer of the vessel
(intima) which causes narrowing and occlusion of the vessel. This is likely due to an increase in proliferating
vascular smooth muscle cells (VSMCs) or endothelial cells (ECs) and extracellular matrix components. Cues
from ECs could cause VSMCs to switch to a phenotype that is proliferative and migrates from media to the
intima, thus contributing to the thickening of the intima. Thus, we hypothesize that dysregulated signaling
between VSMCs and ECs drive MMD pathology. Using MMD patient iPSC-derived ECs and VSMCs, we have
established co-culture model and 3D cellular model by generating vascular organoids. Preliminary co-culture
data show that both MMD ECs and VSMCs are functionally impaired when compared to healthy controls, with
respect to cell proliferation and in vitro angiogenic tube stabilization. In Aim 1, we aim to characterize the
functional properties of MMD iPSC-derived ECs and VSMCs in co-cultures by assessing their ability in cell
proliferation, migration and tube formation in normal and hypoxic conditions. VSMC phenotype switching will be
examined using specific phenotypic markers and contractility assay. We will also characterize vessel structural
characteristics using our established vascular organoids generated from MMD iPSCs. In Aim 2, we will use RNA
sequencing technology to investigate the transcriptome of VSMCs and ECs and identify potential molecular
mediators involved in MMD. Top targets will be validated using quantitative PCR and their expression pattern
will be investigated in our cellular models using immunostaining. Our study will elucidate cell-type specific factors
that may drive MMD pathology. Vascular organoids from MMD may be an efficient human in vitro MMD model
and provide invaluable information on MMD mechanisms. Data from our studies will advance the knowledge in
MMD pathogenesis and open up new avenues of research to yield clinically relevant drug-based methods to
treat MMD.

## Key facts

- **NIH application ID:** 10487543
- **Project number:** 5R21NS121589-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** GARY K STEINBERG
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $196,750
- **Award type:** 5
- **Project period:** 2021-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10487543

## Citation

> US National Institutes of Health, RePORTER application 10487543, Investigating the pathogenesis of Moyamoya Disease using patient derived induced pluripotent stem cells (5R21NS121589-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10487543. Licensed CC0.

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