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Modelling glioblastoma with organoids and assembloids: Opportunities and challenges.
Glioblastoma (GBM) is the most common malignant tumor of the adult central nervous system and is associated with an extremely poor prognosis. Despite standard-of-care treatment, including surgery, radiotherapy, and chemotherapy, mortality rates remain high, highlighting the urgent need for more effective therapeutic strategies. The pronounced intratumoral heterogeneity, highly invasive growth behavior, and strong dependence on the tumor microenvironment complicate both the biological understanding of glioblastoma and the management of therapy resistance. Conventional two-dimensional culture systems and simplified three-dimensional models fail to adequately capture these complex disease characteristics. Recent advances in three-dimensional organoid and assembloid technologies provide physiologically relevant platforms that preserve patient-specific molecular profiles, spatial organization, and tumor-microenvironment interactions. In particular, assembloid systems integrating multiple cellular components enable the investigation of glioblastoma invasion, microenvironment-driven cellular plasticity, and mechanisms of therapeutic resistance. This review provides a critical overview of current two- and three-dimensional in vitro models used in glioblastoma research, with a focus on emerging organoid and assembloid platforms. Their strengths, limitations, and recent innovations are discussed, highlighting their potential to advance translational research and support personalized therapeutic strategies for glioblastoma.
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Bioactive and chemically defined hydrogels with tunable stiffness guide cerebral organoid formation and modulate multi-omics plasticity in cerebral organoids.
Organoids are an emerging technology with great potential in human disease modelling, drug development, diagnosis, tissue engineering, and regenerative medicine. Organoids as 3D-tissue culture systems have gained special attention in the past decades due to their ability to faithfully recapitulate the complexity of organ-specific tissues. Despite considerable successes in culturing physiologically relevant organoids, their real-life applications are currently limited by challenges such as scarcity of an appropriate biomimetic matrix. Peptide amphiphiles (PAs) due to their well-defined chemistry, tunable bioactivity, and extracellular matrix (ECM)-like nanofibrous architecture represent an attractive material scaffold for organoids development. Using cerebral organoids (COs) as exemplar, we demonstrate the possibility to create bio-instructive hydrogels with tunable stiffness ranging from 0.69 kPa to 2.24 kPa to culture and induce COs growth. We used orthogonal chemistry involving oxidative coupling and supramolecular interactions to create two-component hydrogels integrating the bio-instructive activity and ECM-like nanofibrous architecture of a laminin-mimetic PAs (IKVAV-PA) and tunable crosslinking density of hyaluronic acid functionalized with tyramine (HA-Try). Multi-omics technology including transcriptomics, proteomics, and metabolomics reveals the induction and growth of COs in soft HA-Tyr hydrogels containing PA-IKVAV such that the COs display morphology and biomolecular signatures similar to those grown in Matrigel scaffolds. Our materials hold great promise as a safe synthetic ECM for COs induction and growth. Our approach represents a well-defined alternative to animal-derived matrices for the culture of COs and might expand the applicability of organoids in basic and clinical research. STATEMENT OF SIGNIFICANCE: Synthetic bio-instructive materials which display tissue-specific functionality and nanoscale architecture of the native extracellular matrix are attractive matrices for organoids development. These synthetic matrices are chemically defined and animal-free compared to current gold standard matrices such as Matrigel. Here, we developed hydrogel matrices with tunable stiffness, which incorporate laminin-mimetic peptide amphiphiles to grow and expand cerebral organoids. Using multi-omics tools, the present study provides exciting data on the effects of neuro-inductive cues on the biomolecular profiles of brain organoids.
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Vascular organoid model of Hutchinson-Gilford progeria syndrome uncovers repression of the SRF pathway in premature aging.
Vascular aging is a key driver of cardiovascular disease, yet models capturing its complexity in humans are lacking. Hutchinson-Gilford progeria syndrome (HGPS), a premature aging disorder caused by the LMNA mutation, provides a model to study accelerated vascular decline. Here, we developed a blood vessel organoid (BVO) model from HGPS-mutant human embryonic stem cells (hESCs). These BVOs model HGPS vascular defects and reveal significant downregulation of serum response factor (SRF), a trend also observed in the vasculature of naturally aged primates. We show that SRF regulates angiogenesis-related genes, and that its overexpression rescues endothelial function in HGPS organoids. In summary, we establish a 3D human organoid model of vascular aging, identify SRF as a pivotal regulator and provide a powerful platform for discovering geroprotective therapies.
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Allometric Scaling of physiologically-relevant organoids.
The functional and structural resemblance of organoids to mammalian organs suggests that they might follow the same allometric scaling rules. However, despite their remarkable likeness to downscaled organs, non-luminal organoids are often reported to possess necrotic cores due to oxygen diffusion limits. To assess their potential as physiologically relevant in vitro models, we determined the range of organoid masses in which quarter power scaling as well as a minimum threshold oxygen concentration is maintained. Using data on brain organoids as a reference, computational models were developed to estimate oxygen consumption and diffusion at different stages of growth. The results show that mature brain (or other non-luminal) organoids generated using current protocols must lie within a narrow range of masses to maintain both quarter power scaling and viable cores. However, micro-fluidic oxygen delivery methods could be designed to widen this range, ensuring a minimum viable oxygen threshold throughout the constructs and mass dependent metabolic scaling. The results provide new insights into the significance of the allometric exponent in systems without a resource-supplying network and may be used to guide the design of more predictive and physiologically relevant in vitro models, providing an effective alternative to animals in research.
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Human ALS/FTD brain organoid slice cultures display distinct early astrocyte and targetable neuronal pathology.
Amyotrophic lateral sclerosis overlapping with frontotemporal dementia (ALS/FTD) is a fatal and currently untreatable disease characterized by rapid cognitive decline and paralysis. Elucidating initial cellular pathologies is central to therapeutic target development, but obtaining samples from presymptomatic patients is not feasible. Here, we report the development of a cerebral organoid slice model derived from human induced pluripotent stem cells (iPSCs) that recapitulates mature cortical architecture and displays early molecular pathology of C9ORF72 ALS/FTD. Using a combination of single-cell RNA sequencing and biological assays, we reveal distinct transcriptional, proteostasis and DNA repair disturbances in astroglia and neurons. We show that astroglia display increased levels of the autophagy signaling protein P62 and that deep layer neurons accumulate dipeptide repeat protein poly(GA), DNA damage and undergo nuclear pyknosis that could be pharmacologically rescued by GSK2606414. Thus, patient-specific iPSC-derived cortical organoid slice cultures are a reproducible translational platform to investigate preclinical ALS/FTD mechanisms as well as novel therapeutic approaches.
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Towards organoid culture without Matrigel.
Organoids-cellular aggregates derived from stem or progenitor cells that recapitulate organ function in miniature-are of growing interest in developmental biology and medicine. Organoids have been developed for organs and tissues such as the liver, gut, brain, and pancreas; they are used as organ surrogates to study a wide range of questions in basic and developmental biology, genetic disorders, and therapies. However, many organoids reported to date have been cultured in Matrigel, which is prepared from the secretion of Engelbreth-Holm-Swarm mouse sarcoma cells; Matrigel is complex and poorly defined. This complexity makes it difficult to elucidate Matrigel-specific factors governing organoid development. In this review, we discuss promising Matrigel-free methods for the generation and maintenance of organoids that use decellularized extracellular matrix (ECM), synthetic hydrogels, or gel-forming recombinant proteins.
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Biohybrid organoid-robot sensing for olfaction intelligence.
Owing to the remarkable advancements in artificial intelligence (AI), the sensory modalities in artificial systems that characterize human embodiment have received significant attention. However, olfaction remains largely absent in artificial systems, primarily due to several technological challenges. In this study, we aim to advance biomimetic olfactory processing by developing a biohybrid organoid-robot (BOR) system. This system integrates an olfactory organoid-based bioelectronic nose, machine learning (ML) decoders, and an odor-triggered robotic platform. By harnessing the sensitivity and specificity inherent in biological olfactory systems, organoid-based bioelectronic noses present a distinct advantage over traditional electronic noses, facilitating the detection of a wide spectrum of odors at low concentrations with rapid response times. Real-time ML-powered decoding of sensing signals triggers predefined actions in the robotic system, thereby establishing a perception-interpretation-actuation loop that enables the BOR system to detect environmental olfactory cues and execute corresponding physical actions. The research presented herein advances the field towards realizing the sense of smell in systems with truly embodied intelligence.
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Microglia-like Cells Promote Neuronal Functions in Cerebral Organoids.
Human cerebral organoids, derived from induced pluripotent stem cells, offer a unique in vitro research window to the development of the cerebral cortex. However, a key player in the developing brain, the microglia, do not natively emerge in cerebral organoids. Here we show that erythromyeloid progenitors (EMPs), differentiated from induced pluripotent stem cells, migrate to cerebral organoids, and mature into microglia-like cells and interact with synaptic material. Patch-clamp electrophysiological recordings show that the microglia-like population supported the emergence of more mature and diversified neuronal phenotypes displaying repetitive firing of action potentials, low-threshold spikes and synaptic activity, while multielectrode array recordings revealed spontaneous bursting activity and increased power of gamma-band oscillations upon pharmacological challenge with NMDA. To conclude, microglia-like cells within the organoids promote neuronal and network maturation and recapitulate some aspects of microglia-neuron co-development in vivo, indicating that cerebral organoids could be a useful biorealistic human in vitro platform for studying microglia-neuron interactions.
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Biomanufacturing of glioblastoma organoids exhibiting hierarchical and spatially organized tumor microenvironment via transdifferentiation.
Glioblastoma (GBM) is the most aggressive type of brain tumor that originates from glioblastoma stem cells (GSCs). In the brain, GSCs are supported by a tumor microenvironment (TME) residing in the perivascular niche and the hypoxic niche. The GBM TME is highly heterogenous and exhibits complex cell-to-cell interactions. Three-dimensional tumorspheres cultured in stem cell-enriching media is often used as an in vitro model. The GBM tumorspheres retain some of the transcriptional and translational GSC features but often fails to recapitulate intertumor heterogeneity. Here, we developed a simple, matrix-free, and in vivo-like GBM organoids (GBOs) using patient-derived xenograft GBM lines in small-scale bioreactors. Shear stress was optimized to produce highly reproducible GBOs over 1 mm diameter within 4-5 weeks. GBOs exhibited high stemness and strong cell-to-cell interactions compared to conventional tumorsphere cultures. They displayed spatial gradients of hypoxia-inducible factor 1α positive hypoxic cores where CD133-positive cells resided and spatially heterogeneous expression of NOTCH and its ligands. We also observed a self-established, hierarchically organized, and heterogeneous TME by GBM transdifferentiation into endothelial cells, pericytes, and astrocytes. Collectively, we demonstrate the ability to biomanufacture uniformly sized GBOs that recapitulate in vivo GBM TME features that can serve as an improved GBM in vitro model.
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Development of NIR photocleavable nanoparticles with BDNF for vestibular neuron regeneration.
Among nanoparticle platforms, light or photoresponsive nanoparticles have emerged as a promising drug delivery strategy with spatiotemporal control while minimizing off-target effects. The characteristic absorption spectrum of the photoresponsive moiety dictates the wavelength of light needed to activate bond cleavage. However, the low tissue penetration depth limit and short-wavelength ultraviolet (UV) cellular toxicity are considered disadvantageous. This study developed a vestibular ganglion neuron organoid as a model for vestibulopathy. UV and near-infrared (NIR) radiation targeted the inner ear and neural cells, followed by toxicity evaluation. A significantly smaller toxicity of NIR light was confirmed. The photocleavage release of brain-derived neurotrophic factor (BDNF) was used by applying NIR wavelength. The results indicate that polyethylene glycol octamethylene diamine derivative conjugated with leucomethylene blue with an ethanolamine linker nanoparticle can be effectively disassembled and release BDNF when using the 808 nm laser as a trigger. The findings of the cytotoxicity assay suggest that photocleavable nanoparticles (PCNs) and laser irradiation are safe and biocompatible for human-derived and neural progenitor types of cells. Phototriggered BDNF release by NIR laser supported the growth and differentiation of human neural progenitor cells in culture. In addition, the vestibulopathy organoid exhibited a significant regenerative effect. This study harnesses the full potential of NIR laser PCNs to treat vestibular neuropathies.