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Developmental xenocortication using human-derived organoids in mice
Nature
(2026) Cite this article
The inaccessibility of human brain tissue limits the study of human development and function, a challenge that human stem-cell-derived neural models are beginning to address1,2. 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.
Human stem-cell-based models of the nervous system hold promise to examine previously inaccessible aspects of human brain development, reveal mechanisms of disease and identify evolutionary differences between species. For example, guiding human induced pluripotent stem (hiPS) cells to generate three-dimensional (3D) hCOs recapitulates aspects of neurogenesis and gliogenesis of the cerebral cortex in vitro, including the sequential generation of specialized neuronal cell types1,2. Transplantation of hCOs (t-hCO) into the newborn rat cortex results in integration and enhanced maturation of human neurons3, but physical space constraints within the intracranial cavity and competition with the host cortex for establishing connectivity limit their potential. While transplanted hCOs can occupy up to a third of a rat’s cortical hemisphere3, the human-derived neurons develop in the context of extant rat connections. Rodent neurons develop faster than human neurons, so the rapidly maturing host environment may constrain graft proliferation and neural projections. This limitation is particularly salient when modelling neurodevelopmental disorders associated with large-scale distributed circuit dysregulation and altered behavioural output or when testing therapeutics on human neurons in vivo.
To overcome these constraints, we generated an immunodeficient apallial mouse in which the dorsal and medial pallium is genetically depleted at early stages of development. Anatomical studies, magnetic resonance imaging (MRI) and whole-brain single-nucleus RNA-sequencing (snRNA-seq) analysis confirmed that apallial mice lack dorsal and medial pallium derivatives, including neocortex and hippocampus. Transplantation into apallial mice, termed xenocortication, resulted in the growth of a large volume of human-derived neural tissue that recapitulates the cellular diversity of the developing human cerebral cortex. In these xenocortical (XCX) mice, hCOs integrate within the host central nervous system and exhibit spontaneous electrical activity. Unsupervised machine learning applied to spontaneous mouse behaviour using motion sequencing (MoSeq) revealed distinct behavioural repertoires in control and apal