Integrated manufacturing platform for cortical organoids reveals early phosphatase and prefoldin dysregulation in MAPT V337M neurons
Human pluripotent stem cell (hPSC)-derived cortical organoids are powerful models but are often limited by low efficiency, variability, and stress-related artifacts. To address these challenges, we developed a scalable organoid platform with end-to-end quality control (QC) metrics spanning manufacturing and single-cell RNA-sequencing (scRNA-seq), developed using eight MAPT mutation isogenic line sets relevant to frontotemporal dementia (FTD-tau). Using a 96 slit-well format, we achieved ~100% organoid formation across 64 lines. Controlled-release FGF2 enhanced hPSC pluripotency and reduced mesendodermal contaminants, while optimized SB431542 dosing enhanced cortical patterning across lines with variable TGFBR1/ALK5 expression. The resulting organoids displayed transcriptomic profiles and low-stress signatures closely aligned with the developing human cortex. Applying a cortical organoid scRNA-seq index (CortiCOSI), we identified early dysregulation of phosphatase regulators ( PPP2CA, ANP32A ) and the prefoldin subunit PFDN6 in MAPT V337M excitatory neurons before tau hyperphosphorylation and oligomerization. This platform improves scalability, reproducibility, and mechanistic insight in cortical organoid studies.
Authors
- Celeste M M. Karch (ORCID: https://orcid.org/0000-0002-6854-5547)
- M. Catarina Silva (ORCID: https://orcid.org/0000-0001-5421-6673)
- Daniel H. Geschwind (ORCID: https://orcid.org/0000-0003-2896-3450)
- Le Qi (ORCID: https://orcid.org/0000-0003-4832-2271)
- Keith Lane
- Barbara Treutlein (ORCID: https://orcid.org/0000-0002-3299-5597)
- Taylor B. Bertucci (ORCID: https://orcid.org/0009-0008-1017-6807)
- Susan M. Borden (ORCID: https://orcid.org/0009-0001-2361-1686)
- Leander Dony (ORCID: https://orcid.org/0000-0001-5697-6991)
- Brigitte L. Arduini (ORCID: https://orcid.org/0000-0002-8587-3518)
- Kathryn R. Bowles (ORCID: https://orcid.org/0000-0003-3311-5245)
- Steven Lotz
- Carl Alexander Sandhof (ORCID: https://orcid.org/0000-0001-8692-6987)
- Stephen J. Haggarty (ORCID: https://orcid.org/0000-0002-7872-168X)
- Sally Temple (ORCID: https://orcid.org/0000-0001-7301-783X)
- Alison Goate (ORCID: https://orcid.org/0000-0002-0576-2472)
- Ryan Lotz
- Hailey Lotz
- David C. Butler
- Rebecca Chowdhury
- Shona Joy
- Susan K. Goderie
Institutions
- Harvard University (US)
- University of California, Los Angeles (US)
- Washington University in St. Louis (US)
- Helmholtz Zentrum München (DE)
- ETH Zurich (CH)
- Massachusetts General Hospital (US)
- Neural Stem Cell Institute (US)
- UK Dementia Research Institute (GB)
- Ospedale Policlinico San Martino (IT)
- Center for Systems Biology (US)
- Institute of Computational Biology (DE)
- IRCCS Azienda Ospedaliera Metropolitana (IT)
- University of Edinburgh (GB)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- npj Dementia
- Published
- 2026-11-03
- DOI
- https://doi.org/10.1038/s44400-026-00147-y
- Citations
- 19
- Primary Topic
- Pluripotent Stem Cells Research
- Type
- article
- Field-Weighted Citation Impact
- 10.30
Funders
- Michael J. Fox Foundation for Parkinson's Research
- Association for Frontotemporal Degeneration
- New York State Department of Health
- BrightFocus Foundation
- Rainwater Charitable Foundation
- Alzheimer's Society
- UK Dementia Research Institute
- National Institutes of Health
- Tau Consortium
- Medical Research Council
- National Institute on Aging
- National Institute of Neurological Disorders and Stroke