The brain is our most complex organ – and is still only partially understood. Brain organoids, preforms of the entire organ cultivated from stem cells, are supposed to help. Now, for the first time, scientists have created such a brain organoid, which consists of both neurons and glial cells and whose neuronal activity is similar to that of an embryonic human brain – including the first signs of learning ability. These so-called Bioengineered Neuronal Organoids (BENOs) make it possible to gain new insights into the development of the brain, but could also help in testing new therapies.
It consists of billions of brain cells, is flexibly organized and its functions are based on more than just the sum of its parts: Our brain is a fascinating and highly complex organ – and accordingly difficult to fathom. Despite all the advances in neuroscience, studies on animal models and modern imaging methods, many processes and relationships in our thinking organ are still not fully understood. For some time now, researchers have therefore been looking for ways to recreate the development of the human brain “in a test tube”. For this, human cells are usually reprogrammed in such a way that they revert to the undifferentiated state of stem cells. From these cells, in turn, by targeted manipulation of the culture environment, three-dimensional cell clusters can be grown from brain cells, which are already showing the first signs of networking and function.
From the stem cell to the organoid
Researchers working with Maria-Patapia Zafeiriou from the Göttingen University Medical Center have now created a new type of such brain organoids. Their Bioengineered Neuronal Organoids (BENOs) are made from human induced stem cells that are induced to form both neurons and glial cells through pharmacological and electrical stimulation. The latter form the support structure for the neurons and electrically isolate them from one another, but also contribute to the transmission of signals by releasing brain messenger substances such as glutamate. Above all, the star-shaped branched astrocytes under the glial cells are an important functional component of our brain. For higher brain functions, activating and inactivating nerve cells in direct proximity to the glial cells must be closely and dynamically interconnected at the same time. Disturbances in this interconnection are considered to be a possible cause of the clinical symptoms of neurodegenerative diseases.
While growing their brain organoids, Zafeiriou and her colleagues were able to observe how a proto-brain made up of neurons and glial cells gradually developed from precursors. After eight to 15 days, the first markers for neuronal progenitor cells were detectable, from the 18th day the first signs of differentiated neurons appeared, as they report. From the 50th day, the researchers also observed the biomarkers of finished glial cells. While the cell clump gradually formed into a brain organoid, the neurons began to differentiate into different types: “Between the 28th and 60th day, markers for glutamine-, GABA- and catecholamine-producing neurons could increasingly be identified, as well as transcripts linked to synaptic transmission and ion channels, ”the scientists report. The BENOs already showed morphological properties of the human brain.
Plastic reactions
Closer analyzes showed that the functionality of the brain organoids also comes close to an early stage of development of the human brain. When stimulated, the neurons released neurotransmitters and also communicated via electrical signals. In the course of development, the first neural networks formed in which the brain cells communicated with each other, as the researchers report. Zafeiriou and her colleagues were even able to observe signs of neural plasticity – the adaptation of brain activity to repeated stimuli, such as those produced by learning. “Although we are of course far from replicating the human brain in all of its functions, we are fascinated by the observation of cellular processes that are necessary for learning and memory formation in BENOs,” says Zafeiriou.
According to the scientists, their brain organoids could not only provide new insights into the development of the embryonic brain, but are also suitable for researching the loss of learning ability and memory in neurodegenerative diseases. “The first indications of complex, physiological functions in the cultivated neural networks give us hope that we will be able to simulate degenerative diseases of the central nervous system in the laboratory in the future,” explains co-author Wolfram-Hubertus Zimmermann from the University Medical Center Göttingen. “Building on the expected gain in knowledge, it will be possible in the future to develop innovative therapeutic methods for diseases such as Parkinson’s, epilepsy, stroke and dementia.” At the same time, such brain organoids could also be used to test drugs and therapies, or even to grow replacement tissue for the treatment of patients with neurodegenerative diseases, according to the researchers.
Source: Maria-Patapia Zafeiriou (Universitätsmedizin Göttingen) et al., Nature Communications, doi: 10.1038 / s41467-020-17521-w