Modeling Anthracycline-Induced Cognitive Impairment Using iPSC-Derived Brain-On-Chips

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PROJECT SUMMARY Doxorubicin (DOX), a well-established and highly effective chemotherapy drug of the anthracycline class, is commonly used to treat multiple malignancies. Accumulating evidence shows that cancer patients who underwent anthracycline-based chemotherapy showed more severe cognitive impairment than those who received non-anthracycline regimens. However, due to the relative inaccessibility of functional human brain tissues for research, the underlying mechanisms of DOX-induced cognitive impairment remain poorly understood. To that end, in this Alzheimer’s-focused administrative supplement, we aim to use patient-specific induced pluripotent stem cell (iPSC)-derived neurovascular cells in 2D and 3D cultures to model this diseased phenotype in a dish. In Aim 1, we will generate iPSC-brain pericytes and iPSC-brain microvascular endothelial cells (BMECs) from 10 DOX-insensitive and 10 DOX-sensitive patients, and test cell viability, oxidative stress, mitochondrial function, and cytokine secretion in both vascular cell types before and after physiological DOX treatment. In Aim 2, we will use brain-on-chips to generate an in vitro 3D blood-brain barrier-like structure (the neurovascular unit) comprising of isogenic iPSC-pericytes, iPSC-BMECs, iPSC-astrocytes, and iPSC-neurons as a more physiological relevant platform to investigate the effects of cell-cell interaction on DOX-induced BBB integrity disruption. Overall, the platform we will be establishing can serve as a proof-of-principle to test druggable targets that can ameliorate cognitive deficits or various types of neurodegenerative diseases caused by cancer- related treatments.