A phenotypic brain organoid atlas and biobank for neurodevelopmental disorders.

Publication Year:

2025

Authors:

Lu Wang, Yuji Nakamura, Junhao Li, David Sievert, Yang Liu, Toan Nguyen, Prudhvi Sai Jetti, Ethan Thai, Rachel Yibei Zhou, Jiaming Weng, Naomi Meave, Manya Yadavilli, Robyn Howarth, Kevin Camey, Niyati Banka, Charlotte Owusu-Hammond, Chelsea Barrows, Stephen F Kingsmore, Maha S Zaki, Eran Mukamel, Joseph G Gleeson

PubMed ID:

41187745

Funding Grants:

CIRM Graduate Student Training Grant for the Implementation of a Stem Cell Technology and Lab Management Program: Training in Stem Cell Sciences and Regenerative Medicine
CIRM Graduate Student Training in Stem Cell Sciences in the Stem Cell Technology and Lab Management Emphasis of the MS Biotechnology Program

Public Summary:

Thousands of genes are associated with neurodevelopmental disorders (NDDs), yet mechanisms and targeted treatments remain elusive. To fill these gaps, we present a California Institute of Regenerative Medicine (CIRM)-initiated NDD biobank of 352 publicly available genetically diverse patient-derived induced pluripotent stem cells (iPSCs), along with clinical details, brain imaging, and genomic data, representing four major categories of disease: microcephaly (MIC), polymicrogyria (PMG), epilepsy (EPI), and intellectual disability (ID). From 35 representative patients, we studied over 6,000 brain organoids for histology and single-cell transcriptomics. Compared with an organoid library from ten neurotypicals, patients showed distinct cellular defects linked to underlying clinical disease categories. MIC showed defects in cell survival and excessive TTR+ cells, PMG showed intermediate progenitor cell junction defects, EPI showed excessive astrogliosis, and ID showed excessive generation of TTR+ cells. Our organoid atlas demonstrates both conserved and divergent NDD category-specific phenotypes, bridging genotype and phenotype. This NDD iPSC biobank can support future disease modeling and therapeutic approaches.

Scientific Abstract:

Thousands of genes are associated with neurodevelopmental disorders (NDDs), yet mechanisms and targeted treatments remain elusive. To fill these gaps, we present a California Institute of Regenerative Medicine (CIRM)-initiated NDD biobank of 352 publicly available genetically diverse patient-derived induced pluripotent stem cells (iPSCs), along with clinical details, brain imaging, and genomic data, representing four major categories of disease: microcephaly (MIC), polymicrogyria (PMG), epilepsy (EPI), and intellectual disability (ID). From 35 representative patients, we studied over 6,000 brain organoids for histology and single-cell transcriptomics. Compared with an organoid library from ten neurotypicals, patients showed distinct cellular defects linked to underlying clinical disease categories. MIC showed defects in cell survival and excessive TTR+ cells, PMG showed intermediate progenitor cell junction defects, EPI showed excessive astrogliosis, and ID showed excessive generation of TTR+ cells. Our organoid atlas demonstrates both conserved and divergent NDD category-specific phenotypes, bridging genotype and phenotype. This NDD iPSC biobank can support future disease modeling and therapeutic approaches.