Brain organoids: New models to study neural development and disease
ORAL · Invited
Abstract
The human brain, particularly the forebrain, has many features and functions that are distinct to humans. To effectively understand human disease mechanisms and identify novel therapies, it is critical to have access to a human tissue-based model for experimental study. Many clinical trials of neurological disorders have been unsuccessful perhaps because they have been designed based on animal models and have not taken into account some cross-species differences. Human fetal tissue is unquestionably valuable as it is the gold standard to which results need to be compared. However, there are many ethical and practical concerns, including the limited availability of human brain samples particularly at early fetal stages, making it very difficult to conduct controlled, mechanistic experiments and screen for drugs. These considerations illustrate the need for alternative tools to create human brain cells, and ideally tissues with functional neural networks. Consequently, a great deal of attention has been placed on the generation of in vitro models using human pluripotent stem cells (hPSCs) to recapitulate aspects of human development and disease. Recently, several protocols for brain organoids (aka “mini-brain in a dish”), in which hPSCs are induced to form three-dimensional tissue structure that recapitulates the developing brain, have been established. While progress in organoid technology is rapidly advancing, many challenges remain, including rampant batch-to-batch and line-to-line variability, unwanted differentiation into different classes of neural cells and other tissue types, and the paucity of direct comparisons to native human tissue. We established reproducible and efficient methods for cortical organoid differentiation that faithfully recapitulate in vivo neocortical development transcriptionally, structurally, and functionally. We also applied the organoid system to model neurodevelopmental diseases including Congenital Zika Syndrome and Rett Syndrome. Taken together, our study showed a cortical organoid system could recapitulate early human development and be an ideal platform to model disease, providing an unprecedented opportunity to study brain structures with multidisciplinary approaches.
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Publication: 1. Watanabe M, Buth JE, Vishlaghi N, de la Torre-Ubeita L, Taxidis J, Khakh B, Coppola G, Pearson C, Yamauchi K, Gong D, Dai X, Damoiseaux R, Aliyari R, Liebscher S, Schenke-Layland K, Caneda C, Huang EJ, Zhang Y, Cheng G, Geschwind DH, Golshani P, Sun R, and Novitch BG. Self-organized cerebral organoids with human specific features predict effective drugs to combat Zika virus infection. 2017. Cell Reports, 21(2):517-532<br><br>2. Li C, Deng YQ, Wang S, Ma F, Aliyari R, Huang XY, Zhang NN, Watanabe M, Dong HL, Liu P, Li ZF, Ye Z, Tian M, Hong, S, Fan J, Zhao H, Li L, Vishlaghi N, Au C, Liu Y, Lu N, Du P, Qin FXF, Zhang B, Novitch BG, Xu Z, Qin CF, and Cheng G. 25-Hydroxycholesterol protects host against ZIKV infection and its associated mirocephaly. 2017. Immunity, 46(3):1-11.<br><br>3. Samarasinghe RA, Miranda OA, Buth JE, Mitchell S, Ferando I, Watanabe M, Allison TF, Kurdian A, Gandal MJ, Golshani P, Plath K, Lowry WE, Parent JM, Mody I, and Novitch BG. Identification of neural oscillations and epileptic changes in human brain organoids. 2021. Nat Neurosci, 24(10):1488-1500.<br><br>4. Watanabe M, Haney J, Vishlaghi N, Turcios F, Buth JE, Gu W, Collier AJ, Miranda OA, Chen D, <br>Clark A, Plath K, Gandal M, and Novitch BG. TGF? superfamily signaling regulates the state of human pluripotency and competency to create telencephalic organoids. 2022. Stem Cell Reports, 17(10):2220-2238.
