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Revealing the inner workings of organoids.
The mechanisms by which human stem cells self‐organise into brain‐like tissues in 3D organoid culture are poorly understood. In this issue of The EMBO Journal, Renner and Lancaster et al demonstrate that in the absence of external stimuli, human cerebral organoids develop large forebrain structures that display specific landmarks of spatial and temporal patterning, including signalling centres producing known morphogens. The generation of cerebral organoids is therefore likely to reflect normal brain development.
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Nested pediatric low-grade glioma cerebral organoid avatars reveal glutamatergic neuron stromal growth dependency.
Pilocytic astrocytomas (PAs), the most common pediatric brain tumor, grow slowly and depend heavily on their local brain microenvironment, hindering accurate humanized model development. To surmount this barrier, we developed mixed assembloids of PAs nested within human iPSC-cerebral organoids (PANCOs) that recapitulate PA histopathology and growth. Consistent with their cell-intrinsic ERK dependence, MEK inhibition reduces PANCO proliferation, whereas clozapine-N-oxide-activatable neural progenitors integrate into PANCOs, preferentially differentiate into glutamatergic neurons, and increase cell-extrinsic PA proliferation, which is blocked by glutamate receptor inhibition. These accurate in vitro pediatric PA avatars provide tractable platforms to discover and validate PA cell-intrinsic and cell-extrinsic growth dependencies.
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A modular platform for automated organoid culture and longitudinal imaging.
Organoids, 3D tissue cultures that mimic real organs, offer valuable models for research. Traditional culture methods rely on manual feeding and orbital shakers, making them labor-intensive and inconsistent. Microfluidic systems have shown their potential to improve reproducibility by controlling media exchange and culture conditions, yet most still require standard incubators, which limit continuous monitoring due to space and humidity constraints. To address this, we developed a modular platform that integrates automated feeding, real-time imaging, and environmental control, eliminating the need for a conventional incubator. A key feature is a vertically oriented PDMS/glass chip that supports precise media delivery and monitoring while preserving incubation conditions, making it ideal for morphological studies. We demonstrated the platform's ability to maintain metabolic stability and media distribution over time using cerebral organoids. This platform improves organoid research by combining microfluidics, automation, and imaging, enhancing disease modeling, drug testing, and regenerative medicine applications.
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Volumetric compression by heterogeneous scaffold embedding promotes cerebral organoid maturation and does not impede growth.
Although biochemical regulation has been extensively studied in organoid modeling protocols, the role of mechanoregulation in directing stem cell fate and organoid development has been relatively unexplored. To accurately replicate the dynamic organoid development observed in nature, in this study, we present a method of heterogeneous embedding using an alginate-shell-Matrigel-core system. This approach allows for cell-Matrigel remodeling by the inner layer and provides short-term moderate-normal compression through the soft alginate outer layer. Our results show that the time-limited confinement contributes to increased expression of neuronal markers such as neurofilament (NF) and microtubule-associated protein 2 (MAP2). Compared with non-alginate embedding and alginate compression groups, volume growth remains unimpeded. Our findings demonstrate the temporary mechanical regulation of cerebral organoid growth, which exhibits a regular growth profile with enhanced maturation. These results highlight the importance and potential practical applications of mechanoregulation in the establishment of brain organoids. A record of this paper's transparent peer review process is included in the supplemental information.
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Glioblastoma-midbrain assembloid-based Electrophysiological sensor composed of dual-channel flexible Au nanodot patterned electrodes to evaluate cancer drug.
Brain organoids and assembloids have been developed to investigate brain-associated diseases, such as neurodegenerative diseases and brain cancer. However, brain assembloid-based in vitro drug evaluation models remain limited due to the lack of three-dimensional (3D) electrophysiological sensors that are capable of continuously monitoring the changes in drug-induced electrophysiological signals. In this study, we developed a 3D electrophysiological sensor by integrating glioblastoma multiforme (GBM)-midbrain (MB) assembloids with dual-channel flexible gold (Au) nanodot-patterned electrodes, for in vitro drug evaluation with continuous monitoring. Au nanodot-patterned films were fabricated using laser interference lithography and attached to a polymer-based 3D concave mold to form flexible Au nanodot-patterned electrodes, which enhanced electrophysiological signal detection. The GBM-MB assembloid was generated by integrating GBM and MB organoids within a neurotrophin factor-3 (NT3)/gold nanoparticle (GNP)-incorporated hydrogel, which improved electrical conductivity and neural connectivity within the assembloid, leading to increased spike activity. The 3D electrophysiological sensor, consisting of the assembloid on dual-channel flexible electrodes, enabled continuous and independent detection of electrophysiological signals from individual organoids. Both organoids showed increased cancer-induced electrophysiological signals, which were significantly reduced by treatment with Everolimus (a cancer drug), validating the system's effectiveness for dynamic drug evaluation. Electrophysiological signal analysis further revealed the influence of GBM organoid states on MB organoids. The proposed electrophysiological sensors, integrating continuous monitoring of brain assembloid activity with dual-channel flexible electrodes, offers a promising platform for toxicity assessment and drug screening for diverse brain diseases.
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Application of organoid technology in the human health risk assessment of microplastics: A review of progresses and challenges.
Microplastic (MP) pollution has become a global environmental issue, and increasing concern has been raised about its impact on human health. Current studies on the toxic effects and mechanisms of MPs have mostly been conducted in animal models or in vitro cell cultures, which have limitations regarding inter-species differences or stimulation of cellular functions. Organoid technology derived from human pluripotent or adult stem cells has broader prospects for predicting the potential health risks of MPs to humans. Herein, we reviewed the current application advancements and opportunities for different organoids, including brain, retinal, intestinal, liver, and lung organoids, to assess the human health risks of MPs. Organoid techniques accurately simulate the complex processes of MPs and reflect phenotypes related to diseases caused by MPs such as liver fibrosis, neurodegeneration, impaired intestinal barrier and cardiac hypertrophy. Future perspectives were also proposed for technological innovation in human risk assessment of MPs using organoids, including extending the lifespan of organoids to assess the chronic toxicity of MPs, and reconstructing multi-organ interactions to explore their potential in studying the microbiome-gut-brainaxis effect of MPs.
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Translational organoid technology - the convergence of chemical, mechanical, and computational biology.
Successful clinical translation of organoid technology requires insights that extend beyond biology and biochemistry, notably from the fields of mechanical and computational biology. This review highlights recent advances in the organoid field that could potentially accelerate translation. We first review organoid fabrication methods, focusing on engineering approaches that increase organoid reproducibility, controllability, and production ability, as well as the physical conditions, culture media, and extracellular materials that regulate cell signaling and mechanotransduction. We then review computation-based organoid evaluation, including both information acquisition and data mining. Finally, we summarize the limitations of current advances and application horizons as well as the perspective of digital organoids.
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Immersion bioprinting of hyaluronan and collagen bioink-supported 3D patient-derived brain tumor organoids.
Organoids, and in particular patient-derived organoids, have emerged as crucial tools for cancer research. Our organoid platform, which has supported patient-derived tumor organoids (PTOs) from a variety of tumor types, has been based on the use of hyaluronic acid (HA) and collagen, or gelatin, hydrogel bioinks. One hurdle to high throughput PTO biofabrication is that as high-throughput multi-well plates, bioprinted volumes have increased risk of contacting the sides of wells. When this happens, surface tension causes bioinks to fall flat, resulting in 2D cultures. To address this problem, we developed an organoid immersion bioprinting method-inspired by the FRESH printing method-in which organoids are bioprinted into support baths in well plates. The bath-in this case an HA solution-shields organoids from the well walls, preventing deformation. Here we describe an improvement to our approach, based on rheological assessment of previous gelatin baths versus newer HA support baths, combined with morphological assessment of immersion bioprinted organoids. HA print baths enabled more consistent organoid volumes and geometries. We optimized the printing parameters of this approach using a cell line. Finally, we deployed our optimized immersion bioprinting approach into a drug screening application, using PTOs derived from glioma biospecimens, and a lung adenocarcinoma brain metastasis. In these studies, we showed a general dose dependent response to an experimental p53 activator compound and temozolomide (TMZ), the drug most commonly given to brain tumor patients. Responses to the p53 activator compound were effective across all PTO sets, while TMZ responses were observed, but less pronounced, potentially explained by genetic and epigenetic states of the originating tumors. The studies presented herein showcase a bioprinting methodology that we hope can be used in increased throughput settings to help automate biofabrication of PTOs for drug development-based screening studies and precision medicine applications.
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H3K27M drives OPC stemness and intrathecal therapeutic vulnerability in brainstem glioma organoids.
Brainstem gliomas, particularly H3K27M-mutant diffuse midline gliomas (DMGs), lack effective therapies owing to anatomic inaccessibility, intact blood-brain barrier, and treatment resistance. Conventional models have low establishment rates and fail to preserve the native tumor microenvironment, limiting translational study for this rare disease. Here, we established a patient-derived brainstem glioma organoid (BSGO) platform with high success, faithfully recapitulating parental tumor features. Multi-omics and functional assays revealed that DMGs maintain oligodendrocyte precursor cell (OPC) stemness by dysregulating ACTIVIN signaling. To overcome delivery barriers and target stemness, we conducted an intrathecal drug screening and identified triple intrathecal therapy (methotrexate + cytarabine + dexamethasone, TIT) as a potent regimen against DMGs. In DMG patients, organoid-avatar guided personalized therapy induced sustained responses, with TIT-associated reductions in OPC markers reliably tracked by cerebrospinal fluid (CSF) proteomic profiling. Together, our study provides an organoid-based platform for mechanistic investigation and personalized intrathecal therapy screening and proposes TIT as a promising translational strategy for DMG.
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Human organoid tumor transplantation identifies functional glioblastoma-microenvironment communication mediated by PTPRZ1.
Glioblastoma is the most aggressive and deadly form of brain cancer. Here, we leverage our human organoid tumor transplantation (HOTT) co-culture system to explore how extrinsic cues modulate glioblastoma cell types and behavior. HOTT recapitulates core features of major patient tumor cell types and key aspects of neural cell-enriched tumor microenvironment (nTME) gene programs. Our exploration of patient TME interactions preserved in HOTT highlights four receptor-ligand interactions of interest. We knock down all four of these genes in the HOTT microenvironment. We observe that knocking down nTME PTPRZ1, a receptor tyrosine phosphatase implicated in cancer cell migration, results in an increased fraction of mesenchymal cells, enrichment of epithelial-to-mesenchymal gene programs, and an elevated tumor microtube length in co-cultured primary patient tumors. This phenotype is not mediated by PTPRZ1's catalytic activity, suggesting a mechanism of tumor cell fate driven by nTME PTPRZ1, highlighting the strengths of the HOTT system.