Generation of cortical organoids with tunable areal identities by spatial engineering of morphogens

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Grant Application Details

Application Title:

Generation of cortical organoids with tunable areal identities by spatial engineering of morphogens

Public Abstract:
Research Objective

This project is to identify molecular mechanisms for generating different cortical regions using a novel hydrogel platform and brain organoids.


The hydrogel technology to establish localized signals and resulting enhanced cortical organoids would advance 3D human stem cell cultures as tools for biomedical innovation.

Major Proposed Activities

  • Hydrogel optimization for signaling molecule encapsulation. We will utilize a library of hydrogel materials and properties that incorporate signaling molecules as inks for a bioprinter.
  • Assessment of regional markers in cortical organoids interfaced with hydrogel bioscaffolds that encapsulate signaling molecules, using immunohistochemistry, RT-qPCR, and single-cell RNA-sequencing.
  • Precisely and focally localized signaling molecule presentation to cortical organoids, using a bioprinter, to reproducibly form different regions.
  • Characterization of enhanced cortical organoids, using single-cell RNA-sequencing to demonstrate if they better mimic the human fetal cortex, compared to spontaneously formed cortical organoids
  • Identification of novel gene regulatory networks that govern cortical regionalization, using scRNA-sequencing and bioinformatic analyses.
  • Verification of key hub genes identified in Activity 5 by knocking down and overexpressing these genes using electroporation and/or viral delivery methods in cortical organoids.
Statement of Benefit to California:
This project aims to enhance cortical organoids derived from human pluripotent stem cells. Although current cortical organoids recapitulate the developing human fetal cortex, they lack a controlled formation of different regions, including prefrontal and motor cortices. Many neurological disorders, including autism, are differentially affected in distinct cortical regions. Once established, enhanced cortical organoids that can better model disease and pave the way for therapeutic applications.