Scientists at ETH Zurich have broken new ground by growing over 400 types of nerve cells from stem cells in the laboratory. This surpasses previous experiments in which only a few dozen cells could be produced. By systematically experimenting with combinations of morphogens and gene regulators, the researchers were able to replicate the enormous diversity of neurons in the human brain. This breakthrough holds great promise for research into neurological diseases such as Alzheimer’s and Parkinson’s, the development of more accurate models for drug testing and ultimately even for neuron replacement therapies.
Variety of Different Nerve Cell Types
Nerve cells are not just nerve cells. According to the latest calculations, there are several hundred to several thousand different types of nerve cells in the human brain, depending on how finely we differentiate between them. These cell types differ in their function, in the number and length of their cell processes and in the connections between them. They release different messenger substances into our synapses, and depending on the region of the brain – for example in the cerebral cortex or midbrain – different cell types are active.
In the past, when scientists produced nerve cells from stem cells in petri dishes for their experiments, it was not possible to take their enormous diversity into account. Until now, researchers had only developed methods to grow a few dozen different nerve cell types in vitro. They did this using genetic engineering or by adding signaling molecules to activate certain cellular signaling pathways. However, they never came close to the hundreds or thousands of different nerve cell types that actually exist.
Systematic Screening as the Key to Success
“Neurons derived from stem cells are often used to study diseases. Until now, however, researchers have often ignored the exact types of neurons they are working with,” says Barbara Treutlein, Professor at the Department of Biosystems Science and Engineering at ETH Zurich in Basel. However, this is not the best approach for such work. “If we want to develop cell culture models for diseases and disorders such as Alzheimer’s, Parkinson’s and depression, we need to consider the specific type of neuron affected.”
Treutlein and her team have now successfully produced over 400 different types of nerve cells. The scientists have thus paved the way for more precise basic neurological research with cell culture experiments. The ETH researchers achieved this by working with a culture of human induced pluripotent stem cells obtained from blood cells. Using genetic engineering, they activated certain neuronal regulatory genes in these cells and treated the cells with various morphogens, a special class of signaling molecules. Treutlein and her team proceeded systematically and used seven morphogens in different combinations and concentrations in their screening experiments. This resulted in almost 200 different experimental conditions.
Morphogens are messenger substances known from embryonic research. They are not evenly distributed in the embryo, but occur in different concentrations and form spatial patterns. In this way, they determine the position of the cells in the embryo, for example whether a cell is located near the body axis or in the back, abdomen, head or torso. Morphogens therefore help determine what grows where in the embryo. Using various analyses, the researchers were able to prove that they had generated over 400 different types of nerve cells in their experiment. They examined the RNA (and thus the genetic activity) at the level of individual cells as well as the external appearance of the cells and their function: for example, what type of cell extensions they had and in what quantities, and what electrical nerve impulses they emitted.
The researchers then compared their data with information from databases on neurons in the human brain. This enabled them to identify the types of nerve cells produced, for example those found in the peripheral nervous system or in brain cells, as well as the part of the brain from which they originate and whether they perceive pain, cold or movement, and so on.
Research into Severe Neurological Diseases
Treutlein makes it clear that there is still a long way to go before all types of nerve cells that exist can be produced in vitro. Nevertheless, the researchers now have access to a much larger number of different cell types than before. They want to use the in vitro nerve cells to develop cell culture models for research into severe neurological diseases such as schizophrenia, Alzheimer’s, Parkinson’s, epilepsy, sleep disorders and multiple sclerosis. Such cell culture models are also of great interest for pharmaceutical research in order to test the effect of new active substances in cell cultures without animal testing, with the aim of one day being able to cure these diseases.
In the future, the cells could also be used for cell replacement therapy, in which diseased or dead nerve cells in the brain are replaced by new human cells. Before this is possible, however, one challenge still needs to be overcome: In their experiments, the researchers often produced a mixture of several different nerve cell types. They are now working on optimizing their method so that only one specific cell type is produced under the respective experimental conditions. They already have initial ideas on how this could be achieved.