A new method for generating High Quantity brain organoids (Hi-Q) using human induced pluripotent stem cells (hiPSCs) has emerged, opening new doors for the modeling of brain diseases such as microcephaly and glioma invasion, and enhancing drug screening processes. Researchers have demonstrated this approach addresses significant bottlenecks faced by traditional organoid methodologies, which often struggle with issues related to morphological and cellular heterogeneity, as well as poor reproducibility.
The development of these organoids was conducted at the Heinrich-Heine-University, Düsseldorf, with findings recently published by the authors of the article. The method allows for the effective generation of thousands of organoids across multiple hiPSC lines. Not only do Hi-Q brain organoids exhibit consistent cytoarchitecture, cellular diversity, and functionality, but they also minimize cellular stress pathways, which are known to interfere with organoid development and disease modeling.
To achieve this, researchers utilized innovative techniques such as custom-designed microwells, which enable control over the size of the cells being cultured. Omitting the embryoid body stage—previously integral to organoid development—streamlined the process, facilitating the direct transformation of hiPSCs to the neural epithelium. Following this step, the organoids are transferred to spinner-flask bioreactors for large-scale growth, capable of producing approximately 15,373 organoids over 39 batches.
Importantly, the Hi-Q brain organoids can be cryopreserved and re-cultured without losing functional integrity, ensuring their utility across various applications. According to researchers, "Hi-Q brain organoids can be successfully cryopreserved and re-cultured,” highlighting the robustness of this new system.
These organoids were successfully utilized to model distinct developmental defects, including primary microcephaly due to mutations affecting the centrosomal protein CDK5RAP2 and the neurological impact associated with progeria-linked defects from Cockayne syndrome. Notably, patient-derived Hi-Q brain organoids demonstrated characteristic invasion patterns when fused with glioma stem cells (GSCs), allowing researchers to conduct medium-throughput drug screening.
Through this methodology, researchers identified significant therapeutic compounds, Selumetinib and Fulvestrant, as effective inhibitors of GSC invasion, marking promising progress toward targeted therapies for glioblastoma. "We identified Selumetinib and Fulvestrant as potent GSC invasion inhibitors,” the authors noted, reflecting the potential for Hi-Q skimming compounds to reduce tumor aggression.
The novel Hi-Q approach not only refines the generation process of organoids but also enhances their applicability for personalized medicine and targeted drug discovery. Given the substantial number of rare genetic brain diseases—over 10,000—that significantly impact patients, the ability to model such disorders accurately is of utmost importance.
By providing enhanced functionality and reproducibility, Hi-Q brain organoids signify substantial progress toward solving previous challenges faced by scientists. Their development marks a significant advancement within the field of neurodevelopmental disorder research and paves the way for future therapies targeting difficult-to-treat conditions.
Overall, the introduction of the Hi-Q methodology showcases the commitment of the scientific community to innovatively address longstanding barriers within brain organoid research, nurturing hopes for breakthroughs not only for glioma invasion treatment but also for the broader spectrum of brain diseases associated with neurogenetic anomalies.
