Scientists have grown more than 400 types of nerve cells from stem cells

Nerve cells are not just nerve cells. When you look at them in enough detail, the latest estimates suggest that there are several hundred or even several thousand different types of nerve cells in the human brain. These types differ in their functions, the number and length of their processes, and how they connect to each other. They release different neurotransmitters into synapses, and depending on the area of the brain—the cerebral cortex or midbrain, for example—different types of cells are active.

When scientists grew nerve cells from stem cells in petri dishes for experiments, they couldn’t account for all this diversity. Until recently, researchers had developed methods for growing only a few dozen different types of nerve cells in vitro. To do this, they used genetic engineering approaches or added signaling molecules to activate specific intracellular signaling pathways. But they had never come close to capturing the diversity of the hundreds or thousands of different types of nerve cells that exist in the body.

"Neurons derived from stem cells are often used to study diseases. But until now, researchers have often ignored which 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, she says this is not the best approach to such work.

"If we want to develop cell models to study diseases and disorders such as Alzheimer's, Parkinson's and depression, we need to consider the specific type of nerve cell involved in the pathological process."

Systematic screening as a key to success

Treutlein and her team have now successfully produced more than 400 different types of nerve cells, paving the way for more precise fundamental neurological research using cell cultures.

The ETH scientists achieved this by working with a culture of human induced pluripotent stem cells, which were derived from blood cells. In these cells, they genetically engineered certain neuronal regulatory genes and treated the cells with different morphogens – a special class of signaling molecules. Treutlein’s team used a systematic approach: seven morphogens in different combinations and concentrations in their screening experiments. This ultimately yielded almost 200 different sets of experimental conditions.

Morphogens

Morphogens are signaling substances known from studies of embryonic development. They are distributed unevenly in the embryo, and in different concentrations form spatial gradients. Thus, they determine the position of cells in the embryo - for example, whether a cell is closer to the body axis or is located at the back, on the abdomen, in the head or torso area. Accordingly, morphogens help determine which structures will form in different parts of the body.

The scientists used a variety of analysis techniques to show that they had managed to obtain more than 400 different types of nerve cells in the experiment. They studied the RNA (and thus genetic activity) at the level of individual cells, as well as the cells’ appearance and function, such as what types of cell processes they had and what electrical nerve impulses they emitted.

The researchers then compared their data with information from databases of human brain neurons. This allowed them to determine the types of nerve cells that were created, such as peripheral nervous system cells or brain cells, as well as the area of the brain they came from and what these cells are responsible for - perceiving pain, cold, movement, etc.

In vitro neurons for the search for active substances

Treutlein said they are still far from being able to produce in vitro all the types of nerve cells that exist in the body. However, the researchers now have access to many more different types of cells than before.

They want to use neurons grown in vitro to develop cell models for studying serious neurological diseases, including schizophrenia, Alzheimer's, Parkinson's, epilepsy, sleep disorders and multiple sclerosis. Such cell models are also of great interest for pharmaceutical research, allowing the effects of new active compounds to be tested in cell cultures without the use of animals, with the ultimate goal of one day learning how to cure these diseases.

In the future, these cells could also be used for cell replacement therapy, in which diseased or dead brain nerve cells are replaced with new human cells.

But before that can happen, there’s a problem to solve: In their experiments, the researchers often produced a mixture of several different types of nerve cells. They’re now working on optimizing the method so that each experimental condition produces only one specific type of cell. They already have some initial ideas on how to do that.