# Investigating Pericyte Roles in Blood-Brain Barrier Formation

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $367,795

## Abstract

ABSTRACT
The blood-brain barrier (BBB) acts as a signaling and transport interface between the blood and brain. The
BBB begins to form early in embryonic development as the mesoderm-derived vasculature invades the
immature central nervous system (CNS) and acquires BBB characteristics such as tight junctions and a lack of
fenestrae. After further maturation, the adult BBB, with its very low permeability and a wealth of molecular
transport systems, is maintained by interactions with supporting cells of the neurovascular unit (NVU). Recent
studies have indicated the importance of CNS pericytes in BBB formation, with pericytes triggering reduced
transcytosis, reduced expression of leukocyte adhesion molecules and proper tight junction organization.
However, the identity of pericyte-derived factors that can elicit these important changes during BBB formation
are not known. Thus, our understanding of the molecular mechanisms underpinning BBB formation is
incomplete; and in this proposal, we aim to further examine the mechanisms by which brain pericytes impact
BBB formation. A powerful and innovative approach to explore BBB formation is the use of human induced
pluripotent stem cell (iPSC) technology to model the BBB and the associated support cells of the NVU. We will
demonstrate that not only can brain pericytes be differentiated from iPSCs, they can also regulate key BBB
properties in iPSC-derived brain endothelial cells (BMECs). In parallel, using genomics approaches, we have
identified a cohort of pericyte-derived secreted factors, several of which can induce BBB properties in iPSC-
derived BMECs. Combining these approaches, we will examine the mechanisms whereby pericyte-derived
secreted factors can differentially regulate BBB formation in iPSC-derived BMECs. Preliminary data indicate
that one of the pericyte-derived secreted factors, BMP5, can influence hallmark BBB properties known to be
regulated by brain pericytes. Namely, BMP5 can reduce transcytosis and improve tight junction structures in
iPSC-derived BMECs. To further examine the mechanism by which BMP5 regulates BBB formation during
development, we will use genetic mouse models to explore whether BMP5 signaling is necessary for BBB
formation and function. Finally, we will assess whether BMP5 supplementation can be therapeutic in a mouse
model of multiple sclerosis. Understanding the pericyte-derived regulators of BBB formation could yield many
new mechanistic insights regarding brain diseases that have demonstrable pericyte involvement. Knowledge of
the barrier formation pathways could also open new avenues for restoring BBB function in debilitating
neurological disease.

## Key facts

- **NIH application ID:** 10150106
- **Project number:** 5R01NS103844-04
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** ERIC V SHUSTA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $367,795
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10150106

## Citation

> US National Institutes of Health, RePORTER application 10150106, Investigating Pericyte Roles in Blood-Brain Barrier Formation (5R01NS103844-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10150106. Licensed CC0.

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