Innate Immunocompetent hiPSC-Derived Neurospheroids Capture Early CNS Responses to rAAV.
Overview
- iBET Instituto De Biologia Experimental e Biológica Oeiras Portugal
- Instituto De Tecnologia Química e Biológica António Xavier Universidade Nova de Lisboa Oeiras Portugal
- Drug Discovery Sciences Bayer AG Wuppertal Germany
- CNC ‐ Center for Neuroscience and Cell Biology of Coimbra, Molecular Therapy of Brain Disorders Group University of Coimbra Coimbra Portugal
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology University of Liverpool Liverpool UK
- Institute For Interdisciplinary Research (III) University of Coimbra Coimbra Portugal
- GeneT, Gene Therapy Center of Excellence University of Coimbra Coimbra Portugal
- ViraVector–Viral Vectors for Gene Transfer Core Facility University of Coimbra Coimbra Portugal
- Center For Innovative Biomedicine and Biotechnology (CIBB) University of Coimbra Coimbra Portugal
- Faculty of Pharmacy University of Coimbra Coimbra Portugal
Abstract
Gene therapies using adeno‐associated viruses (AAVs) for central nervous system (CNS) disorders face challenges because host immune responses are not represented in classical preclinical models. Here, we present a human‐induced pluripotent stem cell (hiPSC)‐derived innate immunocompetent 3D CNS model that recapitulates neuroinflammatory hallmarks, serving as a platform for preclinical gene therapy development. By utilizing various scales of stirred‐tank bioreactor systems, we generated neurospheroids (iNSpheroids) composed of neurons, astrocytes, and oligodendrocytes, alongside microglial cells (iMGLs) to mimic the neuroimmune axis. These systems enabled large‐scale production of iNSpheroids and subsequent miniaturization for co‐culture experiments and screening of inflammatory stimuli, while maintaining a highly controlled environment. The iMGL‐iNSpheroids demonstrated active neuron‐microglia crosstalk and exhibited distinct inflammatory responses to a series of neuroinflammatory factors. iMGL‐iNSpheroids mounted an early response to rAAV9, which is underscored by the activation of inflammatory pathways (e.g., TNF‐via NF‐κB activation) in glial cell populations. This model offers a valuable tool to dissect neuroinflammatory mechanisms, accelerating gene therapy development.
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
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Data
Data links
- ncbi.nlm.nih.gov/
geo , NCBI; found in the resources table
Data Availability Statement
This study did not generate new unique materials. Single‐nucleus and bulk RNA‐seq data have been deposited at GEO: Bulk RNAseq data accession number GSE299019. snRNA‐Seq data accession number: GSE298806. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE [128] partner repository with the dataset identifier PXD065639.
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 1, 27 September 2026: the first record
Recorded: type, language, journal, pages, dates, 15 authors, 5 keywords, 4 funders, 132 references.
Cite
This paper
Gomes, C. M., Silva, G., Aleixo, M., Gomes, M., Simão, D., Holtkamp, S. J., Lobo, D. D., Harish, P., Jenkins, R., Dahal, L. N., Nobre, R. J., de Pereira de Almeida, L., Trautwein, M., Alves, P. M., & Brito, C. (2026). Innate Immunocompetent hiPSC-Derived Neurospheroids Capture Early CNS Responses to rAAV. Advanced science (Weinheim, Baden-Wurttemberg, Germany), e20408. https://
BibTeX
@article{gomes2026innate
author = {Gomes, Catarina M. and Silva, Gabriela and Aleixo, Mafalda and Gomes, Marta and Simão, Daniel and Holtkamp, Stephan J. and Lobo, Diana D. and Harish, Pradeep and Jenkins, Rosalind and Dahal, Lekh N. and Nobre, Rui J. and de Pereira de Almeida, Luís and Trautwein, Mark and Alves, Paula M. and Brito, Catarina},
title = {{Innate Immunocompetent hiPSC-Derived Neurospheroids Capture Early CNS Responses to rAAV}},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
year = {2026},
month = sep,
pages = {e20408},
publisher = {Wiley},
issn = {2198-3844},
doi = {10.1002/
url = {https://
pmid = {42702874},
pmcid = {PMC13547711}
}
RIS
TY - JOUR
AU - Gomes, Catarina M.
AU - Silva, Gabriela
AU - Aleixo, Mafalda
AU - Gomes, Marta
AU - Simão, Daniel
AU - Holtkamp, Stephan J.
AU - Lobo, Diana D.
AU - Harish, Pradeep
AU - Jenkins, Rosalind
AU - Dahal, Lekh N.
AU - Nobre, Rui J.
AU - de Pereira de Almeida, Luís
AU - Trautwein, Mark
AU - Alves, Paula M.
AU - Brito, Catarina
TI - Innate Immunocompetent hiPSC-Derived Neurospheroids Capture Early CNS Responses to rAAV
T2 - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
J2 - Adv Sci (Weinh)
PY - 2026
DA - 2026/
SP - e20408
SN - 2198-3844
PB - Wiley
DO - 10.1002/
UR - https://
LA - en
ER -
CSL-JSON
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