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Microfluidic device with brain extracellular matrix promotes structural and functional maturation of human brain organoids.

ABSTRACT: Brain organoids derived from human pluripotent stem cells provide a highly valuable in vitro model to recapitulate human brain development and neurological diseases. However, the current systems for brain organoid culture require further improvement for the reliable production of high-quality organoids. Here, we demonstrate two engineering elements to improve human brain organoid culture, (1) a human brain extracellular matrix to provide brain-specific cues and (2) a microfluidic device with periodic flow to improve the survival and reduce the variability of organoids. A three-dimensional culture modified with brain extracellular matrix significantly enhanced neurogenesis in developing brain organoids from human induced pluripotent stem cells. Cortical layer development, volumetric augmentation, and electrophysiological function of human brain organoids were further improved in a reproducible manner by dynamic culture in microfluidic chamber devices. Our engineering concept of reconstituting brain-mimetic microenvironments facilitates the development of a reliable culture platform for brain organoids, enabling effective modeling and drug development for human brain diseases.

SUBMITTER: Cho AN

PROVIDER: S-EPMC8342542 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Recent advancements in tissue engineering suggest that biomaterials, such as decellularized extracellular matrix (ECM), could serve to potentiate the localization and efficacy of regenerative therapies in the central nervous system. Still, what factors and which mechanisms are required from these ECM-based biomaterials to exert their effect are not entirely understood. In this study, we use the brain as a novel model to test the effects of particular biochemical and structural properties by evaluating, for the first time, three different sections of the brain (i.e., cortex, cerebellum, and remaining areas) side-by-side and their corresponding decellularized counterparts using mechanical (4-day) and chemical (1-day) decellularization protocols. The three different brain subregions had considerably different initial conditions in terms of cell number and growth factor content, and some of these differences were maintained after decellularization. Decellularized ECM from both protocols was used as a substrate or as soluble factor, in both cases showing good cell attachment and growth capabilities. Interestingly, the 1-day protocol was capable of promoting greater differentiation than the 4-day protocol, probably due to its capacity to remove a similar amount of cell nuclei, while better conserving the biochemical and structural components of the cerebral ECM. Still, some limitations of this study include the need to evaluate the response in other biologically relevant cell types, as well as a more detailed characterization of the components in the decellularized ECM of the different brain subregions. In conclusion, our results show differences in neuronal maturation depending on the region of the brain used to produce the scaffolds. Complex organs such as the brain have subregions with very different initial cellular and biochemical conditions that should be considered for decellularization to minimize exposure to immunogenic components, while retaining bioactive factors conducive to regeneration. [Figure: see text] Impact statement The present study offers new knowledge about the production of decellularized extracellular matrix scaffolds from specific regions of the porcine brain, with a direct comparison of their effect on in vitro neuronal maturation. Our results show differences in neuronal maturation depending on the region of the brain used to produce the scaffolds, suggesting that it is necessary to consider the initial cellular content of the source tissue and its bioactive capacity for the production of an effective regenerative therapy for stroke.

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Microfluidic device with brain extracellular matrix promotes structural and functional maturation of human brain organoids.

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