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[Electron microscopic and enzyme histochemical investigations on craniopharyngiomas and their tissue cultures (author's transl)].
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Microgravity-cultured glioblastoma organoids integrated with microfluidic chip for CAR-γδ T evaluation.
Tumor organoids mimicking the tumor microenvironment (TME) are key tools for tumor immunity research and personalized cancer therapy development. We integrated microgravity culture with microfluidic chip technology (Micro-GRA& FLU) to establish a platform for evaluating chimeric antigen receptor (CAR)-γδ T cell efficacy under physiological-like conditions. Patient-derived glioblastoma (GBM) cells were microgravity-cultured into glioblastoma organoids (GBOs). Pathological analysis validated GBO similarity to matched GBM in immune cell phenotypes. Microfluidic chips assessed CAR-γδ T cell cytotoxicity against GBOs. The low-cost, easy-to-operate microgravity system generated viable, uniform GBOs that retained GBM TME features. CAR-γδ T cells showed strong cytotoxicity against GBOs in microfluidic chips; individualized combination therapy enhanced their antitumor activity vs. monotherapy. This study establishes a scalable, physiologically relevant Micro-GRA& FLU platform for evaluating CAR-γδ T cell therapies in GBM organoids.
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Modeling microcephaly with cerebral organoids reveals a WDR62-CEP170-KIF2A pathway promoting cilium disassembly in neural progenitors.
Primary microcephaly is caused by mutations in genes encoding centrosomal proteins including WDR62 and KIF2A. However, mechanisms underlying human microcephaly remain elusive. By creating mutant mice and human cerebral organoids, here we found that WDR62 deletion resulted in a reduction in the size of mouse brains and organoids due to the disruption of neural progenitor cells (NPCs), including outer radial glia (oRG). WDR62 ablation led to retarded cilium disassembly, long cilium, and delayed cell cycle progression leading to decreased proliferation and premature differentiation of NPCs. Mechanistically, WDR62 interacts with and promotes CEP170's localization to the basal body of primary cilium, where CEP170 recruits microtubule-depolymerizing factor KIF2A to disassemble cilium. WDR62 depletion reduced KIF2A's basal body localization, and enhanced KIF2A expression partially rescued deficits in cilium length and NPC proliferation. Thus, modeling microcephaly with cerebral organoids and mice reveals a WDR62-CEP170-KIF2A pathway promoting cilium disassembly, disruption of which contributes to microcephaly.
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Human chromosomes and centrioles as nucleating sites for the in vitro assembly of microtubules from bovine brain tubulin.
Treatment of HeLa cells with Colcemid at concentrations of 0.06-0.10 mug/ml leads to irreversible arrest in mitosis. Colcemid-arrested cells contained few microtubules, and many kinetochores and centrioles were free of microtubule association. When these cells were exposed to microtubule reassembly buffer containing Triton X-100 and bovine brain tubulin at 37 degrees C, numerous microtubules were reassembled at all kinetochores of metaphase chromosomes and in association with centriole pairs. When bovine brain tubulin was eliminated from the reassembly system, microtubules failed to assemble at these sites. Similarly, when EGTA was eliminated from the reassembly system, microtubules failed to polymerize. These results are consistent with other investigations of in vitro microtubule assembly and indicate that HeLa chromosomes and centrioles can serve as nucleating sites for the assembly of microtubules from brain tubulin. Both chromosomes and centrioles became displaced from their C-metaphase configurations during tubulin reassembly, indicating that their movements were a direct result of microtubule formation. Although both kinetochore- and centriole-associated microtubules were assembled and movement occurred, we did not observe direct extension of microtubules from kinetochores to centrioles. This system should prove useful for experimental studies of spindle microtubule formation and chromosome movement in mammalian cells.
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Cerebral Organoids Repair Ischemic Stroke Brain Injury.
Stroke is the second leading cause of death and main cause of disability worldwide, but with few effective therapies. Although stem cell-based therapy has been proposed as an exciting regenerative medicine strategy for brain injury, there are limitations. The developed cerebral organoids (COs) represent a promising transplantation source for stroke that remains to be answered. Here, we transplanted COs at 55 days and explored the feasibility in the rat middle cerebral artery occlusion (MCAO) model of stroke. COs transplantation at 6 h or even 24 h after MCAO significantly reduces brain infarct volume and improves neurological motor function. Transplanted COs show the potential of multilineage differentiation to mimic in vivo cortical development, support motor cortex region-specific reconstruction, form neurotransmitter-related neurons, and achieve synaptic connection with host brain via in situ differentiation and cell replacement in stroke. Cells from transplanted COs show extensive migration into different brain regions along corpus callosum. The mechanisms underlying COs transplantation therapy are also associated with enhanced neurogenesis, synaptic reconstruction, axonal regeneration and angiogenesis, and decreased neural apoptosis with more survival neurons after stroke. Moreover, COs transplantation promotes predominantly exogenous neurogenesis in the transplantation periphery of ipsilateral cortex and predominantly endogenous neurogenesis in the hippocampus and subventricular zone. Together, we demonstrate the efficacy and underlying mechanisms of COs transplantation in stroke. This preliminary but promising study provides first-hand preclinical evidence for COs transplantation as a potential and effective intervention for stroke treatment.
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Modeling glioblastoma niche-by-niche: recent advancements in bioengineering of organotypic models of glioblastoma for precision medicine.
Glioblastoma (GBM) represents the most aggressive and recalcitrant primary malignancy of the central nervous system, characterized by profound intratumoral heterogeneity and a formidable capacity for adaptive therapeutic resistance. This phenotypic plasticity is orchestrated by the tumor microenvironment (TME), which functions as a dynamic clockwork mechanism wherein the hypoxic, perivascular, immune, and neural niches act as interconnected, functionally coupled gears. The synergistic activity of this system is fueled by the combined influence of biochemical signals and key biomechanical forces, specifically interstitial fluid flow, matrix stiffness, and oxygen gradients. While traditionalin vivomodels have elucidated foundational biological principles, they frequently fail to recapitulate the human-specific, multi-scale dynamics inherent to GBM pathology, thereby hindering translational progress. This review evaluates recent advancements in bioengineering strategies that transition beyond single-niche isolation toward a modular, 'niche-by-niche' reconstruction of the GBM TME. We highlight the evolving trajectory of microphysiological systems, where advanced 3D culture and biofabrication methods, such as organoids and bioprinted microfluidic constructs, are leveraged to incorporate multifaceted physicochemical cues in a highly controlled and reproducible manner. Furthermore, we address existing technical limitations and identify critical next steps in the field, including the integration of clinically relevant metrics and scalability. Finally, we propose that these engineered ecosystems serve as innovative tools for the advancement of precision oncology, providing a robust framework for tailoring therapeutic interventions to the unique profile of each patient.
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From Organoids to Assembloids: Experimental Approaches to Study Human Neuropsychiatric Disorders.
To understand the pathophysiology of and develop effective therapeutics for brain disorders, some of which may involve uniquely human features of the nervous system, scalable human models of neural cell diversity and circuit formation are essential. The discovery of cell reprogramming and the development of approaches for generating stem cell-derived neurons and glial cells in 3D preparations known as neural organoids and assembloids, both in vitro and following transplantation in vivo, provide new opportunities to tackle these challenges. Here, we outline strengths and limitations of currently available human experimental models as applied to neurological and psychiatric disorders for both environmental and genetic risk factors, and we discuss how these new tools hold promise for accelerating the development of therapeutics.
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Application and prospect of organoids in tobacco product safety and risk evaluation.
In recent years, with the emergence of various types of tobacco products, the safety and risk assessment of tobacco product has become the focus of social attention. Organoids, as a new research model, can simulate the basic properties of tissues and perform normal biological functions in vitro experiments, with the advantages of low cost and high efficiency, it has been tentatively used in the safety evaluation of tobacco products. This review summarizes the concept and types of organoids and introduces the model structure and corresponding fundamentals of organoids in tobacco product safety and risk research. In addition, the effects of tobacco products on phenotypic changes of various organoids (such as lung, intestine, brain, maternal and fetal organoids) and the corresponding mechanisms (including oxidative stress, inflammatory response, etc.) were further summarized. At the same time, the advantages of applying organoids, the development trend and direction of organoids in evaluating tobacco product safety and risk in the future were also summarized. In summary, this review systematically describes the application and prospects of organoids in the safety and risk assessment of tobacco product, which helps researchers draw attention to the important role of organoids in safety and risk assessment of tobacco product, and provides some theoretical and literary foundations for improving people's quality of life.
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Neural cortical organoids from self-assembling human iPSC as a model to investigate neurotoxicity in brain ischemia.
Brain ischemia is a common acute injury resulting from impaired blood flow to the brain. Translation of effective drug candidates from experimental models to patients has systematically failed. The use of human induced pluripotent stem cells (iPSC) offers new opportunities to gain translational insights into diseases including brain ischemia. We used a human 3D self-assembling iPSC-derived model (human cortical organoids, hCO) to characterize the effects of ischemia caused by oxygen-glucose deprivation (OGD). hCO exposed to 2 h or 8 h of OGD had neuronal death and impaired neuronal network complexity, measured in whole-mounting microtubule-associated protein 2 (MAP-2) immunostaining. Neuronal vulnerability was reflected by a reduction in MAP-2 mRNA levels, and increased release of neurofilament light chain (NfL) in culture media, proportional to OGD severity. Glial fibrillary acidic protein (GFAP) gene or protein levels did not change in hCO, but their release in medium increased after prolonged OGD. In conclusion, this human 3D iPSC-based in vitro model of brain ischemic injury is characterized by marked neuronal injury reflected by the release of the translational biomarker NfL which is relevant for testing neuroprotective strategies.
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Transplantation of engineered spinal cord organoids restores functions after spinal cord injury.
Generating functional maturation neural organoids to model degenerative disease or replace large damaged central nervous tissue remains an enormous challenge. Here, we developed a novel blood vessel-mimicking nanomaterial system by combining carboxylated cellulose nanofibres (CCN) with Matrigel to create biosafety scaffolds. These engineered scaffolds demonstrated a remarkable capacity to support the long-term growth over 300 days and functional maturation of neural organoids, enabling the development of centimetre-scale organoids without necrotic cores. CCN-engineered human spinal cord organoids (ChSOs) could self-elongate axon tracts, robustly form axon myelination and establish functional neural networks. Following transplantation, ChSOs demonstrated remarkable differentiation potential, generating multiple subtypes of spinal cord neurons, both dorsal and ventral, that could migrate and integrate sufficiently with the host spinal cord tissue. Notably, these grafted ChSOs secrete the axon guidance factor NTN1, enhancing axonogenesis and facilitating the restoration of sensory and motor functions in mice with complete spinal cord injury. These findings show that ChSOs provide a platform for studying neural development and achieving functional spinal cord repair.