A new study published in Nature Communications delved further into autism by culturing brain-like organoids.
“The human brain is unique, and certain aspects of human brain development and brain diseases are notoriously difficult to study using animal models,” study author Alex Shcheglovitov, PhD, told us. “We wanted to develop a new method to model early aspects of human telencephalic brain development in health and disease. Our approach was to make human brain organoids in a robust and reproducible way.”
The researchers had an idea that started with neural rosettes derived from pluripotent stem cells.
“These are wonderfully self-organizing clusters of neural progenitor cells that can enhance the organization of cells into brain organoids,” Shcheglovitov told us. “We wanted to apply this model to study deficits in neurodevelopmental disorders.”
Genetic abnormalities in a gene called SHANK3 cause autism and other neurodevelopmental deficits. To study these deficits, the researchers made organoids from cells that have the same genetic abnormalities.
“We urgently need reliable models to study the human brain,” Shcheglovitov told us. “We also wanted to develop a methodology for using human and patient-specific cells to understand the cellular and molecular mechanisms that are disrupted in disorders of the human brain. We plan to use brain organoids created from patients’ cells to develop new therapies for those patients.”
The researchers caused human pluripotent stem cells to differentiate into structures called neural rosettes. They then manually isolated individual rosettes and cultured them for up to five months to make organoids. They also generated organoids from stem cells obtained from healthy control individuals and patients with SHANK3 gene mutations.
“We found that organoids made in this way consist of a diversity of cells that organize themselves among themselves in a similar way to how they organize themselves in the brain,” Shcheglovitov told us. “We found that many neurons in organoids mature functionally.”
The researchers also determined that organoids lacking the SHANK3 gene have synaptic and intrinsic deficits associated with disrupted expression of cell adhesion proteins, clustered protocadherins.
“We were very surprised to find a large fraction of inhibitory neurons in organoids derived from single neural rosettes and ependymal- and periendothelial-like cells that, to my knowledge, have never been observed in organoids before,” Shcheglovitov told us. “These cells are important in making the brain an organ isolated from the body.
Of course, the disrupted expression of clustered protocadherins in SHANK3-deficient organoids is very interesting. Potentially, it could explain some of the deficits seen in association with SHANK3 deficiency and this knowledge could contribute to the development of new therapies for patients. However, more work will have to be done on this front.”
The study results provide insights into human telencephalic development and disorders associated with SHANK3 deficiency, including Phelan-McDermid syndrome, autism, intellectual disability, and epilepsy. It is an important step forward in the ability to model human brain development in health and disease and could be useful for future drug development. However, it is important to remember that organoids are not human mini-brains.
Patricia Tomasi is a mother, maternal mental health advocate, journalist, and speaker. She writes regularly for the Huffington Post Canada, focusing primarily on maternal mental health after twice suffering from severe postpartum anxiety. you can find it Huffington Post bio here. Patricia is also an expert patient advisor for the North American-based Maternal Mental Health Research Collective and is the founder of the online peer support group: Facebook postpartum depression and anxiety support group – with more than 1500 members worldwide. Blog: www.patriciatomasiblog.wordpress.com