# "Building a robust organoid platform to study the developmental potential and physiology of human specific cortical cell types"

> **NIH NIH RF1** · HARVARD UNIVERSITY · 2020 · $1,801,797

## Abstract

Abstract
The goal of this proposal is to develop robust in vitro human cell-derived microphysical systems which faithfully
represent key features of the developing human neocortex in vivo. Our work addresses three key challenges
that have limited the development of these systems to date: (1) Building robust and reproducible organoids
at high throughput. To obtain meaningful, statistically significant results from genetic and non-genetic
perturbations, it is necessary to develop organoid systems which are robust and can be reproducibly assayed in
large numbers. (2) Determining in vivo relevance to human neocortex. The utility of organoid systems is
defined by the degree to which they reproduce key aspects of human brain development that are not
recapitulated by model organisms. (3) Monitoring and perturbing activity longitudinally in situ. To address
fundamental questions about cerebral cortex development in either health or disease, it is necessary to capture
and experimentally influence the trajectories of cellular activity across the three-dimensional volume of
developing organoids through chronic recordings and perturbations.
We overcome these challenges by merging three research teams whose expertise spans microfluidics and
microelectromechanical systems, bioengineering and stem cell biology, computational and systems biology, and
theoretical physics. We exploit novel technologies we have developed independently including: (1) microprinting,
droplet encapsulation and microfluidic-based sorting methods to build and enrich for organoids with the selected
cell types and geometry at high throughput, (2) in situ single cell RNA sequencing and computational mapping
methods to determine the robustness of cell type composition and in vivo relevance against previously obtained
in vivo fetal tissue data, and (3) 3D embedded soft microelectrode technology that grows and stretches with the
developing tissue to chronically monitor and perturb electrical activity over the course of development.
Here, we propose to integrate, employ, and build upon these inventions to further conduct basic research on a
unique aspect of human brain development. The cerebral cortex is dramatically expanded and gyrated in humans
versus other closely related species. Outer radial glial (oRG) progenitors have been implicated in this expansion.
We have previously identified molecular markers that define these cell types, built and tested a reporter human
embryonic stem cell line that drives GFP in these cell types, and developed a novel viral barcoded library that
allows us to establish lineage relationships using single-cell sequencing. Here, we will determine the
developmental potential of these human-specific oRG cells. Specifically, we will determine the contribution of
the differentiated oRG progeny to cerebral cortex architecture, cell types, circuit connectivity, and developmental
trajectory. The success of this proposal will result in a robust reproducible pipeline to bu...

## Key facts

- **NIH application ID:** 10049141
- **Project number:** 1RF1MH123948-01
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Jia Liu
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,801,797
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10049141

## Citation

> US National Institutes of Health, RePORTER application 10049141, "Building a robust organoid platform to study the developmental potential and physiology of human specific cortical cell types" (1RF1MH123948-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10049141. Licensed CC0.

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