Developmental xenocortication using human-derived organoids in mice
10 affiliations
- 1Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
- 2Stanford Brain Organogenesis Program, Wu Tsai Neurosciences Institute & Bio-X, Stanford, CA, USA
- 3Department of Neurosurgery, Stanford University, Stanford, CA, USA
- 4Department of Bioengineering, Stanford University, Stanford, CA, USA
- 5BCBL-Basque Center on Cognition, Brain and Language, Donostia-San Sebastián, Spain
- 6IKERBASQUE-Basque Foundation for Science, Bilbao, Spain
- 7Department of Pathology, Stanford University, Stanford, CA, USA
- 8Department of Psychology, Stanford University, Stanford, CA, USA
- 9Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA. [email protected]
- 10Stanford Brain Organogenesis Program, Wu Tsai Neurosciences Institute & Bio-X, Stanford, CA, USA. [email protected]
Abstract
. Transplantation of neural organoids into rodent hosts enables the in vivo study of aspects of human neurodevelopment and circuit function, alongside behavioural phenotyping of the host animals. However, spatial limitations and competition with host circuits constrain the integration of neural organoids, which is critical for studying disease. Here we establish a transplantation platform using a genetic strategy to effectively deplete glutamatergic neurons from mouse neocortex and hippocampus (apallial) and neonatally engraft the cortical cavity with human stem-cell-derived cortical organoids (hCO) to generate xenocortical mice. This leads to robust graft growth with hCOs occupying most of the cortical volume and generating a diversity of human cortical cell types, including layer 5 extratelencephalic projection neurons. Human cortical neurons integrate with the mouse nervous system, and in vivo cortical graft-wide calcium imaging and electrophysiological analyses revealed patterns of organized activity resembling developing circuits. Behavioural analyses of apallial and xenocortical mice revealed broadly preserved locomotion alongside selective differences in limb coordination and altered organization of spontaneous behaviour. Lastly, this platform enabled behavioural readouts in a model of injury to developing human cortical cells. We envision that xenocortication will be useful for obtaining circuit- and behaviour-level readouts using human neurons to study neurodevelopment, model disease and develop therapeutics.
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BibTeX
@article{kaganovsky2026developmental,
title = {{Developmental xenocortication using human-derived organoids in mice}},
author = {Konstantin Kaganovsky and Kevin W. Kelley and Tilo Gschwind and Paul M. Harary and John Kochalka and Alexander D. White and Garikoitz Lerma‐Usabiaga and Xiaoyu Chen and Omer Revah and Felicity Gore and Ayano Aoyama and Jennifer L. Shadrach and Se‐Jin Yoon and Alfredo M. Valencia and Satoe Ogawa and Noah Reis and Hannes S. Vogel and Brian Arie Wandell and Julia A. Kaltschmidt and Iván Soltész and Karl A. Deisseroth and Sergiu P. Pașca},
journal = {Nature},
year = {2026},
month = sep,
doi = {10.1038/s41586-026-11032-2},
url = {https://doi.org/10.1038/s41586-026-11032-2},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Developmental xenocortication using human-derived organoids in mice
AU - Konstantin Kaganovsky
AU - Kevin W. Kelley
AU - Tilo Gschwind
AU - Paul M. Harary
AU - John Kochalka
AU - Alexander D. White
AU - Garikoitz Lerma‐Usabiaga
AU - Xiaoyu Chen
AU - Omer Revah
AU - Felicity Gore
AU - Ayano Aoyama
AU - Jennifer L. Shadrach
AU - Se‐Jin Yoon
AU - Alfredo M. Valencia
AU - Satoe Ogawa
AU - Noah Reis
AU - Hannes S. Vogel
AU - Brian Arie Wandell
AU - Julia A. Kaltschmidt
AU - Iván Soltész
AU - Karl A. Deisseroth
AU - Sergiu P. Pașca
PY - 2026
DA - 2026/09/16
JO - Nature
DO - 10.1038/s41586-026-11032-2
UR - https://doi.org/10.1038/s41586-026-11032-2
AB - . Transplantation of neural organoids into rodent hosts enables the in vivo study of aspects of human neurodevelopment and circuit function, alongside behavioural phenotyping of the host animals. However, spatial limitations and competition with host circuits constrain the integration of neural organoids, which is critical for studying disease. Here we establish a transplantation platform using a genetic strategy to effectively deplete glutamatergic neurons from mouse neocortex and hippocampus (apallial) and neonatally engraft the cortical cavity with human stem-cell-derived cortical organoids (hCO) to generate xenocortical mice. This leads to robust graft growth with hCOs occupying most of the cortical volume and generating a diversity of human cortical cell types, including layer 5 extratelencephalic projection neurons. Human cortical neurons integrate with the mouse nervous system, and in vivo cortical graft-wide calcium imaging and electrophysiological analyses revealed patterns of organized activity resembling developing circuits. Behavioural analyses of apallial and xenocortical mice revealed broadly preserved locomotion alongside selective differences in limb coordination and altered organization of spontaneous behaviour. Lastly, this platform enabled behavioural readouts in a model of injury to developing human cortical cells. We envision that xenocortication will be useful for obtaining circuit- and behaviour-level readouts using human neurons to study neurodevelopment, model disease and develop therapeutics.
SN - 0028-0836
SN - 1476-4687
ER -