Speaker
Description
Introduction
The infections, exogenous chemicals, such as drugs1, environmental pollutants and industrial chemicals, may affect the biological processes of the central nervous system as well as its structural, cellular, and molecular function2 and eventually lead to neuroinflammation3 as well as neurotoxicity4. Neuroinflammation is the common cause of numerous neurological disorders, including Alzheimer's disease, and multiple sclerosis. Despite its clinical significance, the intricate cellular and molecular events underpinning neuroinflammation remain incompletely understood, partly due to the lack of physiologically relevant human-based models. Cerebral organoids5 have emerged as powerful three-dimensional in vitro models that recapitulate key aspects of human brain development and architecture. However, conventional organoid systems lack the dynamic microenvironment and mechanical cues present in vivo. Here, we present an advanced cerebral organoid-on-chip platform that enables the controlled study of neuroinflammatory processes, with a particular focus on the often-overlooked but critical remodeling of the extracellular matrix (ECM) within the brain parenchyma.
Methods
Herein, we describe an organoid-on-chip system, which integrates microfluidic control to mimic vascular perfusion and interstitial flow, thereby better simulating the mechanical forces that influence ECM dynamics in the inflamed brain.
Results
Using this platform, we demonstrate that exposure to pro-inflammatory stimuli induces substantial remodeling of the ECM, including collagen, elastin and glycosaminoglycans (GAGs), alongside changes in expression levels of cytokines. Importantly, we show that ECM remodeling precedes and amplifies canonical cellular responses associated with neuroinflammation, such as microglial activation.
Discussion
By emphasizing the role of ECM alterations in the progression of neuroinflammation, our cerebral organoid-on-chip model provides a transformative platform for dissecting the complex interplay between the cellular and extracellular compartments of the human brain. This system not only advances our fundamental understanding of neuroinflammatory mechanisms but also offers a promising avenue for preclinical testing of novel therapeutics aimed at preserving ECM homeostasis and promoting brain tissue resilience. For future work, biosensor integration might be considered for real-time monitoring of soluble factors6.
Acknowledgement: The funding provided by TUSEB through 40153 project is highly appreciated.
References
(1) Saglam-Metiner, P., … Yesil-Celiktas, O. ICU patient-on-a-chip emulating orchestration of mast cells and cerebral organoids in neuroinflammation. Communications Biology, 2024, 7, 1627
(2) Yaldiz, B., Saglam-Metiner, P., Yesil-Celiktas, O. Decellularized extracellular matrix-based biomaterials for repair and regeneration of central nervous system Expert Reviews in Molecular Medicine 2022, 23, e25
(3) Saglam-Metiner, P., … Yesil-Celiktas, O. Differentiation of neurons, astrocytes, oligodendrocytes and microglia from human induced pluripotent stem cells to form neural tissue-on-chip: a neuroinflammation model to evaluate the therapeutic potential of extracellular vesicles derived from mesenchymal stem cells. Stem Cell Reviews and Reports, 2024, 20, 413-436
(4) Saglam-Metiner, P., … Yesil-Celiktas, O. Humanized brain organoids-on-chip integrated with sensors for screening neuronal activity and neurotoxicity. Microchimica Acta, 2024, 191 (1), 1-25
(5) Saglam-Metiner, P., … Yesil-Celiktas, O. Spatio-temporal dynamics enhance cellular diversity, neuronal function and further maturation of human cerebral organoids. Communications Biology, 2023, 6 (1), 173
(6) Cecen, B., …. Yesil-Celiktas, O., Mostafavi, E., Bal-Ozturk, A. Biosensor Integrated Brain-on-a-Chip Platforms: Progress and Prospects on Clinical Translation. Biosensors and Bioelectronics, 2023, 225, 115100
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