# Modeling developmental gradients and supportive tissue signaling networks using iPSC-derived forebrain organoids embedded in fluidic hydrogels

> **NIH NIH RF1** · VANDERBILT UNIVERSITY · 2020 · $2,347,168

## Abstract

PROJECT SUMMARY
Understanding of many aspects of the human brain is currently limited due to the lack of appropriate model
systems that recapitulate the heterogenous nature of the human brain and the ethical and practical limitations
of working with human brain tissue from patients. To overcome these challenges, we employ three-dimensional
brain organoids, derived from human pluripotent stem cells, that recapitulate key features of human cortical
development. Current approaches to engineer higher levels of organization in human brain organoids,
however, are still quite limited, with fusion of two organoids of disparate specification (assembloids) being the
most common approach. While a basic level of self-organization has been achieved, these models do not
mimic the signaling that occurs during human forebrain formation or the resulting cortical organization seen at
similar fetal developmental states. Another missing component in current organoid systems are the meninges,
known to be a fundamental driving factor in cortical development. Our goal is to increase the level of
complexity and organization in human brain organoids and, additionally, to understand and mimic the
contribution of the meningeal cells to cortical development.
In Aim 1, we will develop a platform using fluidic channels within a large hydrogel to expose embedded
organoids to user-defined gradients of soluble morphogens. We will employ well-established hydrogel
materials as well as a novel bioinstructive hydrogel modified with N-cadherin extracellular peptide epitope (this
material can be patterned with channels, exhibits physiological stiffness, and early studies indicate is suitable
for organoid embedding). We propose to use these platforms to mimic cues occurring during development and
thereby direct an embedded human brain organoid to polarize and to exhibit higher-order cortical organization.
In Aim 2, we plan to elucidate and mimic the contribution of the meninges to cortical development. We will fuse
murine meninges to brain organoids, and characterize the thickness and composition of the subventricular and
intermediate progenitor zones as well as the cortical plate using immunohistochemistry, scRNAseq and mass
cytometry. We will also develop new strategies to differentiate human neural crest stem cells into human
meningeal-like cells. We will then expose assembloids and polarized organoids from Aim 1 to meningeal tissue
and meningeal-derived soluble signaling factors and determine their effects on polarization and interneuron
migration.
Completion of these Aims will pave the way for the next generation of human brain organoid research,
enabling higher degrees of complexity and more biomimetic organization to facilitate new insight into human
brain development and pathology, as well as to rationalize treatments for neurological disorders.

## Key facts

- **NIH application ID:** 10049470
- **Project number:** 1RF1MH123971-01
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Leon Marcel Bellan
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,347,168
- **Award type:** 1
- **Project period:** 2020-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10049470

## Citation

> US National Institutes of Health, RePORTER application 10049470, Modeling developmental gradients and supportive tissue signaling networks using iPSC-derived forebrain organoids embedded in fluidic hydrogels (1RF1MH123971-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10049470. Licensed CC0.

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