Neural Stem Cells

Using advanced pluripotent stem cell-derived 3D organoid models of the human brain to study neurodevelopmental disorders and identify new therapeutic approaches.

Our lab is interested in understanding the cellular and molecular basis of human brain development and disease by using pluripotent stem-cell-derived 3D brain organoid models that closely mimic the cellular complexity, tissue architecture and connectivity of the developing human brain.

Human brain development largely occurs in utero and is therefore inaccessible for investigation. Most of what we know about this process comes from studies in rodents. However, many aspects of human brain development reflect species-specific events that cannot be fully investigated in other animal models.

The recent emergence of cellular models of the human brain, in the form of 3D brain organoids, represents a significant advance in modelling human brain development in vitro and provides an opportunity to understand how abnormalities in this process lead to neurodevelopmental disorders, a large group of conditions which include:

• Autism spectrum disorder
• Intellectual disability
• Attention Deficit Hyperactivity Disorder (ADHD)
• Infantile epilepsies.

Current treatments for these conditions aim at lifelong symptom management, a strategy necessitated by a lack of knowledge of underlying causes.

By combining advanced 3D brain organoids and innovative high-throughput single-cell genomic and transcriptomic technologies, our lab aims to gain insights into cell-type specific developmental abnormalities associated with neurodevelopmental disorders, to ultimately identify novel effective treatments for children affected by these conditions.

Our projects

Developing more advanced 3D organoid models of the human cerebral cortex.

3D pluripotent stem cell-derived organoids hold unprecedented promise for investigating neurodevelopmental disorders in vitro. However, the utility of current organoid systems is limited by the spectrum of cell types they generate and, therefore, the complexity of conditions that can be modelled.

Building on the knowledge of human embryonic brain development, this project aims to develop an advanced brain organoid system that incorporates enhanced cellular and neural circuit complexity.

The development of a more complex organoid model will enable to investigation of the neurobiology behind a larger spectrum of neurodevelopmental disorders and to realize the full potential of brain organoids as a discovery platform.

Modelling autism and other neurodevelopmental disorders by using 3D brain organoid models.

Neurodevelopmental disorders are a large group of conditions that result from insults occurring during critical periods of early brain development. Despite the increased knowledge of the genetic underpinnings of these conditions, the specific alterations caused by single disease gene variants to the developing human brain are still largely unknown.

In this project we will leverage 3D brain organoid models to identify disease-specific developmental abnormalities associated with neurodevelopmental disorders, with a focus on autism spectrum disorder, intellectual disability, and infantile epilepsy.

By taking advantage of high throughput single-cell profiling approaches, we aim to identify the specific cell types and molecular mechanisms affected in neurodevelopmental disorders, to drive the design of effective therapies for these conditions.

Developing high-throughput in vitro drug screenings for neurodevelopmental disorders.

Brain organoids provide a unique opportunity to find new treatments for neurodevelopmental disorders. However, their application for large-scale drug screening has encountered major roadblocks due to the scarce reproducibility of most organoid models, and the lack of analysis methods that fit high-throughput screening requirements.

By taking advantage of our highly reproducible brain organoids and the automated high-throughput platforms at the MCRI disease modelling facility, we aim to develop automated systems for high-throughput drug screening for neurodevelopmental disorders in brain organoids.

By identifying compounds that revert specific disease-associated phenotypes, we aim to develop new treatments for a variety of neurodevelopmental disorders, to ultimately implement organoids into drug discovery pipelines.

Funding

• Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW (Grant Number NNF21CC0073729)
• The Human Frontier Science program (HFSP)
• The Sarah and Lachlan Murdoch Fellowship
• The Thyne Reid Foundation
• The Samuel Nissen Foundation

Featured publications

• Paulsen B*, Velasco S^*#, Kedaigle AJ*, Pigoni M*, Quadrato G, Deo A, Adiconis X, Uzquiano A, Sartore R, Yang SM, Simmons SK, Symvoulidis P, Kim K, Tsafou K, Podury A, Abbate C, Tucewicz A, Smith S, Albanese A, Barrett L, Sanjana NE, Shi X, Chung K, Lage K, Boyden ES, Regev A, Levin JZ, Arlotta P^#. Autism genes converge on asynchronous development of shared neuron classes.  Nature, 2022. 602, 268-273.

• Uzquiano A*, Kedaigle AJ*, Pigoni M, Paulsen B, Adiconis X, Kim K, Faits T, Nagaraja S, Antón-Bolaños N, Gerhardinger C, Tucewicz A, Murray E, Jin X, Buenrostro J, Chen F, Velasco S, Regev A, Levin JZ, Arlotta P^#. Single-cell multiomics atlas of organoid development uncovers longitudinal molecular programs of cellular diversification of the human cerebral cortex. bioRxiv 2020.11.10.376509, 2022.

• Velasco S, Paulsen B, Arlotta P. 3D brain organoids: studying brain development and disease outside the embryo. Annual Review Neuroscience, 2020. 43: 375–389.

• Velasco S, Kedaigle AJ, Simmons SK, Nash A, Rocha M, Quadrato G, Paulsen B, Nguyen L, Adiconis X, Regev A, Levin JZ, Arlotta P^#. Individual brain organoids reproducibly form cell diversity of the human cerebral cortex. Nature, 2019. 570(7762): 523-527.

• Velasco S*, Ibrahim MM*, Kakumanu A*, Garipler G, Aydin B, Al-Sayegh MA, Hirsekorn A, Abdul-Rahman F, Satija R, Ohler U^#, Mahony S^#, Mazzoni EO^#. A multi-step transcriptional and chromatin state cascade underlies motor neuron programming. Cell Stem Cell, 2017. 20(2), 205-217.

*Denotes equal authors; #denotes corresponding authors