Cerebral organoids at the air-liquid interface generate nerve pathways with a functional output

Brain organoids, sometimes also called mini-brains or brain organoids, have become an important and useful tool for understanding the development and disease of the human brain. They have the potential to model brain functions, such as the transfer of information between neurons, but their growth has been limited by restrictions. Today, the Madeline Lancaster group of the Division of Cell Biology at LMB has demonstrated for the first time that brain organoids can direct muscle movements. In collaboration with the group Marco Tripodi and the group Emmanuel Derivery, both members of the LMB, and researchers from the University of Cambridge, they have made significant advances in this area.

The brain organoids are three-dimensional tissues generated by directed differentiation of human stem cells. The resulting neural precursor tissue spontaneously self-organizes into structures and layers resembling the early human embryonic brain. Their growth, however, is limited, both in terms of size and shelf life, as they do not form blood vessels through which nutrients and oxygen are supplied. This prevented the study of subsequent neuronal development.

Usually, the cells are kept submerged in a nutrient rich liquid medium, which provides limited access to oxygen and therefore limits growth. Stefano Giandomenico, researcher of the Madeline Group, has helped develop a method of growing a slice of brain organoids on a porous support membrane, so that the tissue lies at the same time. 39, air-liquid interface. This gives access to the nutrient rich liquid media below and oxygen from the air above. This kept the mini-brain model longer in the dish, so that it could still ripen.

Stefano observed neuronal maturation in the organoid cerebral slice using long-term live microscopy and electrode networks to measure neuronal activity, allowing researchers to see patterns of connectivity between different regions of the mini-brain. Specifically, they placed a piece of mouse spinal cord and an adjacent dorsal muscle near the organoid to see if the neurons of the slice of the mini-brain would grow to connect with it. Not only have some neurons of the organoid developed and connected to the spinal cord, but, what is remarkable, neurons in mini-brain projection could stimulate muscle contractions, just as do motor neurons do in our own body. This is the first demonstration of a functional production of brain organoid tissues in a bowl.

The ability of this model to be used to study how neurons connect in the brain and with the spinal cord could have important implications for our understanding of a range of diseases. In particular, neuronal connectivity defects are thought to be at the root of various psychiatric diseases, including schizophrenia, autism, and depression. Similarly, this model could shed light on conditions in which connectivity is disrupted, such as stroke or dementia. Although this new approach allows a better maturation of the mini-brains, they are still very small and do not have the complete repertoire nor the organization of the brain regions necessary for a higher cognition. Nevertheless, they have the potential to significantly increase our knowledge and understanding of neuronal development.

Provided by
Medical Research Council