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Scientists comment on a study, published in Nature, that reports on work where scientists have transplanted human brain derived organoids into the brains of mice.
From our friends at the German SMC
Prof Moritz Helmstaedter, Head of the Department of Connectomics, Max Planck Institute for Brain Research, Frankfurt am Main, said:
Context of the study
“This study reports on a highly artificial construct: mice from which the cortical neurons were genetically removed, so that neuron organoids derived from human stem cells could subsequently grow into the area of the now-emptied cerebral cortex. The study then demonstrates that these human-cell-based nerve cells integrate to a certain extent into the mouse brain and show functional activity.”
Added value for the field of research
“The mammalian brain is a highly complex structure in which the interaction of neurons, glial cells and other cells, the formation of extensive synaptic connections, as well as spatial conditions, the accessibility of other nerve cells and the influence of the immune system all play an important role. Many of the processes relevant here are not yet understood. It is therefore not possible, based on current knowledge, to assess whether the tissue hybrid of mouse and human constructed here actually replicates human brain properties, or only exhibits certain similarities based on superficial criteria. The significance for basic research should therefore be assessed as moderate.”
From our friends at the German SMC
Prof Simon Schäfer, Professor for Advanced Organoid Systems for Mental Health Research, Technical University of Munich (TUM), said:
The study’s added value and comparison with previous work
“The 2022 study transplanted brain organoids into newborn rats because the thalamocortical and corticocortical connections are not yet fully established at that stage, and already demonstrated functional integration. The conceptual difference in this new work is that it creates a developmental niche, rather than transplanting into an already established cortex. The development of the mouse cortex is largely genetically suppressed, whilst subcortical structures are preserved. This eliminates the competition for connections that otherwise arises because human nerve cells mature slowly and the host neurons are already well-connected by the time the human cells begin to form synapses. The progress thus lies in the extent to which this is achieved, rather than in the principle itself, as the study builds consistently on work by numerous groups, such as those from the laboratories of Fred Gage, Pierre Vanderhaeghen, Magdalena Götz and Mark Hübener.”
Integration of human nerve cells into the mouse brain
“In this study, the integration is well documented at the cellular and anatomical levels, but not functionally.
“Fibres from the graft extend into subcortical structures; meanwhile, mouse neurons form connections with the graft, and mouse interneurons are found within the human tissue. Such connections are a necessary condition for functional integration, but do not yet constitute proof, particularly as the graft remains immature and its network activity is similar to that of developing neural tissue rather than that of a mature cortex. What is particularly relevant for research is that here, human nerve cells mature over a period of months within a perfused tissue complex and remain accessible, which makes it possible to study development and damage responses in vivo.”
Use of the mouse model in research
“I see this as a complement to existing In-vitro models. Organoids and assembloids in culture dishes remain the method of choice for mechanistic questions, throughput and experimental accessibility. The transplantation model complements them where maturation, vascularisation and integration into a living nervous system are required, for example when investigating the damage response of human nerve tissue.”
Ethical aspects
“The handling of ethical issues is documented in this work, including bioethical advice obtained in advance and a specially convened external committee with patient representation. Established frameworks exist, notably the guidelines of the International Society for Stem Cell Research (ISSCR) [IV] and the 2021 report by a specially appointed working group of the National Academies of Sciences, Engineering, and Medicine. In this context, transplants are performed in postnatal animals, for which the ISSCR guidelines require additional expert review and ongoing monitoring of the animals. For non-human primates, the framework is restrictive, as the ISSCR guidelines state that they should only be used if more distantly related species are insufficient for the research question. Under Directive 2010/63/EU, great apes must not, as a rule, be used in animal experiments.”
From our friends at the German SMC
Prof Jürgen Knoblich, Deputy Scientific Director and Senior Researcher, Institute of Molecular Biotechnology, Vienna, Austria, said:
Added Value for the Field of Research
“The significance of this work lies primarily in the technique. The authors demonstrate that a mouse’s entire cerebrum can be replaced by human organoids. While in all previous chimera experiments only small parts of the brain were replaced, the destruction of the mouse’s nerve cells has now created the necessary space to enable complete colonization of the cerebrum by human nerve cells.
“However, the idea that this is a mouse with a human brain is not entirely accurate. First, the human cells continue to develop at their species-specific rate, which is much slower than that of the mouse brain. At the end of the experiments, these cells still correspond to an embryo in the second trimester of pregnancy. Secondly, the results regarding cognitive aspects are rather surprising. On the one hand, it is remarkable how little the mouse’s behavior changes fundamentally when the cerebrum is destroyed. On the other hand, cognitive processes can only be partially preserved by the human cells. The resulting chimeras are therefore of limited use for studying human cognitive processes, and it is doubtful that the new model will play a major role in the research process.
Integration of Human Neurons into the Mouse Brain
“Yes, the study clearly and convincingly shows that the human cells fully integrate into the mouse’s nervous system. That in itself is no surprise. It had already been shown that individual human neurons or even human organoids connect with the nervous system of a mouse or rat and even actively participate in information processing.
Use of the Mouse Model in Research
“The relevance of this new work remains to be seen. Such transplantation experiments are very labor-intensive, ethically problematic, and, above all, do not serve the main goal of organoid research, namely to create alternatives to animal testing. In fact, they even raise additional ethical concerns.
“It must be emphasized, however, that the studies were ethically reviewed according to strict, actually exemplary criteria and were ethically monitored by several committees—both within and outside the participating institution. Research of this kind is subject to strict ethical guidelines, under which potential ethical problems are weighed against the possible benefits for curing diseases, both before and during the experiments.
Transferability to other primates
“Similar transplantation experiments in primates would be extremely difficult to justify at this time. Stem cell research is governed worldwide by guidelines of the International Society for Stem Cell Research*. Most scientific journals have committed to using these as the basis for publishing such work. These guidelines, for example, prohibit any intervention in the human germline. Creating human-primate chimeras falls under Category 2 according to these guidelines, meaning they would have to undergo a rigorous ethical review process. I can hardly imagine that research of this kind would be approved, as there is no discernible medical benefit. Furthermore, the same technique would not be applicable to primates, and any other technology would involve procedures that completely exceed any reasonable ethical framework.
“Human-to-human transplants in which such a large portion of the brain would be replaced are entirely unimaginable. However, human-to-human transplants of a small number of nerve cells are already taking place for therapeutic purposes, for example, to treat Parkinson’s disease.”
[ISSCR – International Society for Stem Cell Research (2025): ISSCR Guidelines for Stem Cell Research and Clinical Translation. Version 1.2; August 2025.
From our friends at the Australian SMC
Prof Cedric Bardy, Matthew Flinders Professor in the College of Medicine and Public Health at Flinders University
“This new study takes human tissue transplantation in rodents to another level by attempting to replace an entire region of a mouse brain with human cells. Innovating preclinical models is vital, and the work builds on recent success transplanting human brain organoids grown in Petri dishes into rodent brains, which demonstrated that over a few months after transplantation, the host brain vascularises the organoids and accelerates the maturation of the human neural tissue (Mansour et al. 2018; Revah et al. 2022; Schafer et al. 2023).
The problem is that new therapeutics with highly promising potential in traditional animal models almost always fail in human clinical trials. Despite our rapidly growing understanding of human brain anatomy and function, therapeutic progress in neurology has largely come to a frustrating standstill. Meanwhile, brain disorders are on the rise in our ageing societies, and for most, no cure is available. The community now increasingly realises that more human-centric preclinical models are needed alongside existing approaches.
The good news is that we have made incredible advances in tissue bioengineering over the past ~15 years. We can now generate live human neural tissue in the laboratory from skin cells obtained from patients or healthy donors; one powerful example is “human brain organoids”, which are live neural cells that self-assemble in 3D and, when patient-derived, they retain the donor’s genetic background and can reproduce important aspects of disease biology. However, like animal models, they have limitations: they are incomplete replicas of organs, or parts of an organ, growing in isolation in a Petri dish and therefore lacking the benefits of a complete living organism. This study aims to bridge this gap by combining the advantages of human neural organoids with those of living rodent organisms.
This study is another important pioneering step towards optimising such hybrid models, but much work remains. Although this hybrid model addresses some limitations of both human tissue in a Petri dish and non-human animal models, it also creates its own technical limitations. For example, artificially removing critical parts of the mouse brain, the neocortex and hippocampus, is a drastic approach that is highly disruptive and may introduce factors that complicate therapeutic translation. Creating these hybrid systems with human cells and animals also raises new ethical concerns, which the authors have clearly considered carefully and take seriously. Yet these ethical and current technical concerns may limit the scalability of such models and their global uptake. However, to succeed in finding cures for complex and devastating neurological disorders, such as dementia, we must diversify our preclinical models to discover and test new candidate therapeutics. As such, this study is an important technological step forward.”
From our friends at the Australian SMC
*NEW COMMENT* Prof Adeel Razi, Professor of Computational Neuroscience at the Turner Institute for Brain and Mental Health, School of Psychological Sciences at Monash University, said:
“Kaganovsky et al. genetically removed most of the mouse cortex and filled the vacancy with human-derived, lab-grown, brain cell cultures (i.e. the brain organoids). They show extended large-scale integration of human brain tissue in the mouse host. They then recorded brain-wide activity of human brain cells in a living mouse. This is a very elegant and ambitious study with profound implications for understanding human brain development and disease.
The proposed system creates an unusual experimental platform for studying biological intelligence. It will help disentangle what properties of human cortical organisation are intrinsic to the human brain from what is imposed by the developmental phase and surrounding mouse host brain circuitry.
However, we should be cautious here: the functional integration of human-derived brain cells is not a proxy for its functional equivalence. The grafted human brain tissue lacks features of mature human brain tissue. And the recorded behaviour emerges from the interactions of the human cortex and the remaining mouse subcortex. Hence the limitation of the technique is that it is difficult to know whether the grafted human brain cells are necessary or sufficient for a particular observed behaviour. This means while the engineered niche in the mouse brain that makes grafting of human tissue possible is the main advance, it also becomes its most important limitation when studying extrapolation to normal human brain development.
Nevertheless, the proposed platform is particularly useful for studying developmental injury and neurodevelopmental diseases, like ADHD and autism, and also testing interventions across integrated human brain tissue.
However, I would be very cautious not to describe this as a “human brain in a mouse”, but rather a hybrid brain system containing developing human brain cells within an overwhelmingly mouse brain. This new hybrid system is also simply not enough to call it to have human-like cognition or consciousness.
The ethical concerns will increase with the increased maturity and scale of these grafting methods, and with the extent of the functional integration of human tissue in a non-human host.
To me here the most interesting question is not whether the mouse brain has been “humanised” but what happens to human brain computation when human brain cells develop and learn within a mouse world.”
From our friends at the Australian SMC
*NEW COMMENT* Dr Rodrigo Suarez, Associate Professor in an Australian Research Council Future Fellow and Group Leader of the Brain Evo-Devo Laboratory, School of Biomedical Sciences and Queensland Brain Institute at The University of Queensland, said:
“This work by the Pașca lab (Stanford University, USA) presents an elegant way to study aspects of human cerebral cortex development by transplanting human-derived stem-cell organoids into a new genetic mouse line that completely lacks a cortex and hippocampus (termed ‘apallial’ mice, which show conserved survival and behaviours despite lacking half of brain volume).
This method avoids potential competition of the grafted human tissue with the faster-developing rodent host brain, as reported in 2022 by the same group, where xenotransplanting human organoids into the developing rat brain resulted in integrated functional networks.
Interestingly, human cells were incorporated into the ‘cortexless’ mouse brain cavity, suggesting that an intact host tissue is not required. Of note, however, this integration only resembles broad aspects of human cell types and connectivity, rather than faithfully recapitulating features of the human brain.
Therefore, its value rests in modelling selected aspects of brain neurodevelopmental and neurodegenerative conditions in a living model, which allowed the authors to probe for physiological, anatomical and behavioural aspects of such conditions that would otherwise be impossible to study in vitro, as well as to devise new therapeutic strategies, including personalised medicine via patient-derived organoids, as shown by the same group in 2024 for Timothy syndrome.
The current paper expands the range of possibilities to model complex human brain diseases, for example, by including environmental insults like low oxygen and by providing better integrated functional connections, such as from motor neurons in the cortex to their spinal targets.”
Danielle Hamm, Director of the Nuffield Council on Bioethics, said:
“This research offers huge potential to deepen our understanding of neurological development and treat disease, but as these human-animal models advance we must ensure exploration of the associated ethical questions keeps pace.
“In our recent review of neural organoids, we found a lack of coordinated best practice and ethical guidance across the field. This is why we have acted to form a professional alliance to develop shared standards and called for public engagement on this topic. It is through this that we will question how far this research should go, and identify the safeguards needed to appropriately balance societal values and scientific opportunity.”
Dr Tim Viney, Associate Professor of Neuroscience, University of Oxford, said:
“This work builds upon their earlier study whereby they transplanted human cortical organoid tissue into the developing rat cerebral cortex 1 demonstrating that the cells from the organoid integrated into the host brain.
“The advance here is they now use a genetic strategy to generate mice that have a depleted cerebral cortex, then transplant the human cortical organoid tissue into the brains of these mice. This remains technically challenging in terms of reducing variability when injecting the cortical organoid cells (4 injections per mouse), but they use fairly standard neurosurgical techniques that will be familiar to most rodent neurophysiologists/neuroanatomists.
‘Acortical’ mice are not a new concept2, generated mice that lack a large proportion of the cerebral cortex. This remains an active area of research, e.g. Zheng et al3used such mice to show they can still perform complex behavioural tasks, which makes for an interesting discussion on the roles of the cortex – the cortex only functions because it is integrated with the rest of the brain.
“I remain cautious about such studies, as these are high risk models that depend on the successful transplantation of viable cells that developed within the organoids. It is still not fully clear to me the methods for preparing the organoids for transplantation, but I think the cells from the organoids are not organised into ‘circuits’ when they are injected in to the mice, rather they are free in solution, hence it is tricky to understand how they become integrated in the host.
“Note that the organoids themselves do not represent the complexities of the human brain, despite the expression of familiar molecular markers and structural characteristics of brain cells. The advantage of organoids comes from the genetic background of the donor, and the possibility to manipulate certain genes to see how mutations can affect particular cellular pathways. But they are not ‘brains in a dish’, as the connectivity is highly artificial (and typically simplified with minimal cell types). The authors themselves state as well the mismatch between the relatively rapid development of the mouse versus the much longer developmental trajectory of human cells.
“They used a clever strategy to virally label cells in the organoids prior to transplantation, followed by adapting an existing technology of rabies tracing from the organoid graft. Otherwise, most of the techniques alone are quite standard, including behavioural tests, electrophysiology, histology.
“The most informative and still gold standard way to investigate the human brain network organisation and activity is using acute ex vivo slice recordings 4 – tissue is removed during neurosurgery then the living tissue can be kept alive (with all its local circuits intact) for at least 12 hours for physiological and anatomical studies. The other complementary technique is in vivo recordings in patients (e.g. epilepsy patients awaiting surgery5).”
References:
[1] Revah et al 2022 https://www.nature.com/articles/s41586-022-05277-w
[2] Kim et al 2010 https://www.sciencedirect.com/science/article/pii/S089662731000190X
[3] Zheng et al 2026 preprint, https://www.biorxiv.org/content/10.64898/2026.08.30.747945v1.full
[4] Somogyi et al 2025 https://pubmed.ncbi.nlm.nih.gov/39810425/
[5] Jacobs et al 2007 https://pubmed.ncbi.nlm.nih.gov/17409248/
From our friends at SMC Spain
Iván Fernández Vega, Senior Lecturer in Pathological Anatomy at the University of Oviedo, Scientific Director of the Principality of Asturias Biobank (BioPA) and Coordinator of the Organoids Hub within the ISCIII’s Biomodels and Biobanks Platform, said:
Does the press release accurately reflect the study?
“Generally speaking, yes. The press release correctly conveys the main innovation of the work, which is the creation of a model in which human cortical organoids grow and integrate extensively into the brain of a mouse with a very significant depletion of its own cortex. The graft comes to account for around 92 per cent of the measured cortical tissue and establishes connections with various structures of the nervous system.
Is the study of high quality? Are the conclusions supported by robust data?
“Yes. It is a technically very comprehensive study that combines histology and immunohistochemistry, single-cell and spatial transcriptomics, magnetic resonance imaging, neuronal tracing, calcium imaging, electrophysiology and behavioural studies. The use of independent approaches that converge in the same direction greatly strengthens the conclusions. They examine the phenomenon from different levels. The authors also use appropriate controls, analyse sex where possible, and note that the experiments and analyses were carried out in a blinded manner wherever feasible.
“Some of the more sophisticated experiments are carried out with only a few animals, so some findings will need to be replicated in larger cohorts and with a greater number of cell lines.
How does this work fit in with the existing evidence?
“It is a logical progression from this group’s previous work. It had already been demonstrated that human cortical organoids transplanted into the brains of rodents could vascularise, mature and integrate better than in culture. The novelty here is the elimination of much of the competition from the recipient animal’s cortex, creating a space in which the human tissue can grow much more extensively and form a widespread network. The aim, therefore, is not to replace conventional organoids, but to overcome some of their main in vitrolimitations.
Have you taken confounding factors into account? Are there any significant limitations?
“The authors have made a considerable effort to control for confounding factors through the use of control groups, comparison with apallial mice without grafts, analysis by sex and different experimental approaches. However, significant limitations remain. The graft remains immature: it lacks canonical cortical lamination, complete arealisation and an interneuronal composition equivalent to that of the mature human cortex. Furthermore, although there is anatomical integration and neuronal activity, it cannot yet be stated that human neurons are necessary or sufficient to produce specific behaviours in the animal.
“I would add another point from a pathological perspective: the graft increases in volume by approximately 4.7-fold between two and three months, but the study is not designed to establish when this growth stabilises. In models derived from pluripotent cells intended to be maintained over long periods, it will be important to characterise the kinetics and long-term safety of proliferation.
It is also interesting from the perspective of the 3Rs: here, the organoids do not replace the animal, but are integrated into it to create a human-animal hybrid model. It could help reduce the number of animals if it allows more information to be obtained per experiment, but that remains to be demonstrated.
What are the implications for the real world?
“The immediate application is not clinical. This is fundamentally a new experimental model. Its main utility could lie in studying neurodevelopmental processes, injuries such as perinatal hypoxia, and certain neurological diseases using human cells integrated into a living nervous system, and subsequently evaluating potential treatments. The study serves as a proof of concept, demonstrating that hypoxic stress produces a marked response in the grafted human tissue and measurable functional changes in the animal.
“In the medium term, the value will lie in determining which human diseases it actually reproduces better than current models and whether the results are reproducible across different iPSC lines, laboratories and protocols‘.”
* ‘Developmental xenocortication using human-derived organoids in mice’ by Konstantin Kaganovsky et al. was published in Nature at 16:00 UK time on Wednesday 16th September
DOI: https://doi.org/10.1038/s41586-026-11032-2
Declared interests
Prof Moritz Helmstaedter: “There are no conflicts of interest.”
Prof Simon Schäfer: “My laboratory at the Centre for Organoid Systems at TUM works both in vitro with human iPSC-based brain organoids and assembloids, and on transplantation approaches for stem cell-derived neural tissue and immune cells.”
Prof Jürgen Knoblich: “I am the inventor of several patents that protect ‘cerebral organoid’ technology, a technology similar to the cell culture technique used in these experiments. I am a partner in a biotech company that uses this technology for drug development.”
Prof Cedric Bardy: Cedric declares that he is Founder and Director of Brain Organoid Therapeutics
Prof Adeel Razi: Adeel has declared no conflicts of interest.
Dr Rodrigo Suarez: Rodrigo has not declared any conflicts of interest.
Dr Tim Viney: I have no interests to declare except that I know one of the authors (Soltesz) who I regard highly. I have not worked directly with organoids but these are my views as a neuroanatomist/neurophysiologist.
Dr Iván Fernández Vega: “I have no conflicts of interest relating to this study. My scientific work includes working with organoid models and I am co-leader of the Organoid Hub at the Carlos III Health Institute.”