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Peer-reviewedCC BY-NC-NDnpj Dementia

Integrated manufacturing platform for cortical organoids reveals early phosphatase and prefoldin dysregulation in MAPT V337M neurons

  • Taylor B. Bertucci1,2
  • Kathryn R. Bowles3,4
  • Steven Lotz1,2
  • Shiraz Bheda1,5
  • Le Qi6,7,2
  • Farhad Farjood1,2
  • Katherine Whitton1,2
  • Susan K. Goderie1,8
  • Susan M. Borden1,2
  • Amelia Rossi1,2
  • Catherine Hamann1,2
  • Kate Tubbesing1,2
26 more authors
  • Jared Rogalski1,2
  • Dylan Murphy1,2
  • Chiara Pedicone9,2
  • Laura Maria Oja10,2
  • Keith Lane1,11
  • Ryan Lotz1,11
  • Hailey Lotz1,11
  • Jack Huber1,11
  • Rebecca Chowdhury1,12
  • Shona Joy1,13,5
  • Michael Miller1,8
  • Carl Alexander Sandhof1,2
  • Brigitte L. Arduini1
  • Thomas R. Kiehl1
  • Heide F. B. Murray14
  • Carl Alexander Sandhof14
  • M. Catarina Silva14
  • Stephen J. Haggarty14
  • Leander Dony15,16
  • Alison Goate16
  • Barbara Treutlein15
  • Celeste M M. Karch17
  • Daniel H. Geschwind6,7
  • Alison Goate10
  • Jeffrey Stern1
  • Sally Temple1
17 affiliations
  1. 1Neural Stem Cell Institute, Albany, NY USA
  2. 2Neural Stem Cell Institute, Discovery Drive, Rensselaer NY 244
  3. 3UK Dementia Research Institute at the University of Edinburgh, Edinburgh Bioquarter, Edinburgh, UK
  4. 4UK Dementia Research Institute at the University of Edinburgh, Edinburgh Bioquarter, Edinburgh, UK, EH16 4SB
  5. 5Program in Neurogenetics, Department of Neurology, and Department of Human Genetics David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
  6. 6Institute for Precision Health, University of California Los Angeles, Los Angeles, CA USA
  7. 7Program in Neurogenetics, Department of Neurology, and Department of Human Genetics David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA USA
  8. 8Dept. of Genetics & Genomic Sciences, Ronald M. Loeb Center for Alzheimer's disease, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy place, New York, NY 10029
  9. 9Dipatrimento di Neuroscienze sperimentali, IRCCS Azienda ospedaliera metropolitana, Policlinico San Martino, Genova, Italy
  10. 10Dept. of Genetics & Genomic Sciences, Ronald M. Loeb Center for Alzheimer's disease, Icahn School of Medicine at Mount Sinai, New York, NY USA
  11. 11Department of Neurology, Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
  12. 12Department of Psychiatry, Knight Alzheimer Disease Research Center, Washington University in St Louis, St Louis, MO, USA
  13. 13Institute for Precision Health, University of California Los Angeles, Los Angeles, CA, USA
  14. 14Department of Neurology, Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
  15. 15Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland
  16. 16Institute of Computational Biology, Computational Health Center, Helmholtz Munich, Neuherberg, Germany
  17. 17Department of Psychiatry, Knight Alzheimer Disease Research Center, Washington University in St Louis, St Louis, MO USA
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{bertucci2026integrated,
  title = {{Integrated manufacturing platform for cortical organoids reveals early phosphatase and prefoldin dysregulation in MAPT V337M neurons}},
  author = {Taylor B. Bertucci and Kathryn R. Bowles and Steven Lotz and Shiraz Bheda and Le Qi and Farhad Farjood and Katherine Whitton and Susan K. Goderie and Susan M. Borden and Amelia Rossi and Catherine Hamann and Kate Tubbesing and Jared Rogalski and Dylan Murphy and Chiara Pedicone and Laura Maria Oja and Keith Lane and Ryan Lotz and Hailey Lotz and Jack Huber and Rebecca Chowdhury and Shona Joy and Michael Miller and Carl Alexander Sandhof and Brigitte L. Arduini and Thomas R. Kiehl and Heide F. B. Murray and Carl Alexander Sandhof and M. Catarina Silva and Stephen J. Haggarty and Leander Dony and Alison Goate and Barbara Treutlein and Celeste M M. Karch and Daniel H. Geschwind and Alison Goate and Jeffrey Stern and Sally Temple},
  journal = {npj Dementia},
  year = {2026},
  month = nov,
  doi = {10.1038/s44400-026-00147-y},
  url = {https://doi.org/10.1038/s44400-026-00147-y},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Integrated manufacturing platform for cortical organoids reveals early phosphatase and prefoldin dysregulation in MAPT V337M neurons
AU  - Taylor B. Bertucci
AU  - Kathryn R. Bowles
AU  - Steven Lotz
AU  - Shiraz Bheda
AU  - Le Qi
AU  - Farhad Farjood
AU  - Katherine Whitton
AU  - Susan K. Goderie
AU  - Susan M. Borden
AU  - Amelia Rossi
AU  - Catherine Hamann
AU  - Kate Tubbesing
AU  - Jared Rogalski
AU  - Dylan Murphy
AU  - Chiara Pedicone
AU  - Laura Maria Oja
AU  - Keith Lane
AU  - Ryan Lotz
AU  - Hailey Lotz
AU  - Jack Huber
AU  - Rebecca Chowdhury
AU  - Shona Joy
AU  - Michael Miller
AU  - Carl Alexander Sandhof
AU  - Brigitte L. Arduini
AU  - Thomas R. Kiehl
AU  - Heide F. B. Murray
AU  - Carl Alexander Sandhof
AU  - M. Catarina Silva
AU  - Stephen J. Haggarty
AU  - Leander Dony
AU  - Alison Goate
AU  - Barbara Treutlein
AU  - Celeste M M. Karch
AU  - Daniel H. Geschwind
AU  - Alison Goate
AU  - Jeffrey Stern
AU  - Sally Temple
PY  - 2026
DA  - 2026/11/03
JO  - npj Dementia
DO  - 10.1038/s44400-026-00147-y
UR  - https://doi.org/10.1038/s44400-026-00147-y
AB  - 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.
SN  - 3005-1940
ER  -