Speaker: A/Professor Silvia Velasco
Murdoch Children's Research Institute
Melbourne
 

Title: Unlocking the potential of brain organoids for understanding and treating neurodevelopmental disorders


Abstract: Pluripotent stem cell-derived organoids represent a significant advance in modelling human brain development and disease in vitro. However, the application of organoids to understand and find new therapies for brain diseases has been impeded by the scarce reproducibility and scalability of these models, and the challenge of identifying reliable pathological phenotypes suitable as readouts in high-throughput drug screenings. We addressed these issues by establishing a new highly standardised protocol that generates brain organoids with consistent morphology, encompassing shape, size, structure, and cellular composition. Bright-field imaging, immunohistochemistry, and single-cell RNA-sequencing analysis of individual organoids showed remarkable reproducibility across different organoids, cell lines and experimental batches. Over time, organoids generate a large collection of cell types resembling those found in the developing human forebrain. These include diverse types of neural progenitors, excitatory projection neurons, inhibitory interneurons, as well as late-born astrocytes and oligodendrocytes. We leveraged the reproducibility of this new organoid model to set up a fully automated system for the generation and high-throughput screening of brain organoids. By using this automated platform, we showed that forebrain organoids haploinsufficient for the histone methyltransferase KMT5B, which is associated with various neurodevelopmental disorders, show increased size recapitulating megalencephaly observed in patients, highlighting the potential of our organoid platform to identify reliable disease phenotypes. Finally, high-throughput screening of forebrain organoids treated with a library of FDA-approved epigenetic compounds revealed that individual drugs induce reproducible alterations in organoid growth and development, further validating the robustness of our new brain organoid platform for large-scale drug screenings. Overall, our work offers new understanding of the role of epigenetic regulation during normal forebrain growth and development and paves the way to implement brain organoids into future drug discovery programs to identify potential therapies for neurodevelopmental disorders.

 

About Neuroscience Seminars

Neuroscience seminars at the QBI play a major role in the advancement of neuroscience in the Asia-Pacific region. The primary goal of these seminars is to promote excellence in neuroscience through the exchange of ideas, establishing new collaborations and augmenting partnerships already in place.

Seminars in the QBI Auditorium on Level 7 are held on Wednesdays at 12-1pm, which are sometimes simulcast on Zoom (with approval from the speaker). We also occassionally hold seminars from international speakers via Zoom. The days and times of these seminars will vary depending on the time zone of the speaker. Please see each seminar listed below for details. 

 

Neuroscience Seminars archive 2005-2018