How cells decide their fate as a fetus develops

Neural crest cells are a very plastic type of cell that exists during early embryonic development in the same domain that will give rise to the spinal cord. They generate numerous types of cells, including nerve cells, pigmented cells, facial bone cells and muscle cells. Now, for the first time, researchers have found out how these cells decide on the role they will take. The research shows that the cells must continually decide whether to move in the direction of becoming one specific type of cell. If a cell does not do this, it has the opportunity to develop into another type of cell.

This discovery is important in understanding how different types of tissue develop as the fetus develops and may help in better understanding some types of cancer in which the decision-making process towards becoming one type of cell or another malfunctions.

Ultimately, the discovery may also help in developing new approaches in regenerative medicine, in which doctors in the future could make replacement tissue in the laboratory and transplant it into people who have lost their hearing, for example, or have had sections of their intestines removed as a result of severe infection.

“Basically, we asked ourselves: ‘How do cells know what they will become?’. Our study answered this question. We can now see where the cells come from and what decisions they make to become several types of specialized cells,” explains a co-author, Maria Eleni Kastriti, Postdoctoral Fellow, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.

The new study was recently published in Science.

The environment determines the fate of cells

Neural crest cells can develop into many types of cells: bone cells in the ocular cavities, bone cells in the ears, jaw and teeth, glial cells that protect nerve cells, skin pigment cells, nerve cells in the head just outside the skull and nerve cells in the autonomic and enteric nervous systems.

When neural crest cells develop towards a particular type of cell as the fetus develops, the cells migrate to the location in the body where they are needed.

Maria Eleni Kastriti’s research shows that the cells are not preprogrammed to become any specific type of cell. Instead, the cells are induced to develop in one direction or another as they migrate.

The environment during migration determines how the cells develop: for example, a neuron-derived signal in the base of the brain influences the first migrating cranial neural crest cells to become precisely bone cells.

Researchers hypothesize that growth factors in the environment of the neural crest could influence groups of genes that determine the fate of each individual cell. For example, one group of genes might promote a cell to become a nerve cell and another group of genes tries to maintain the cell in the undifferentiated state.

“Different groups of cells constantly interact, and the gene expression within neural crest cells oscillates without the cell finally deciding its fate. However, when the environment is right, the gene expression is steered in one direction or another and then the cell begins to transform,” explains Maria Eleni Kastriti.

Cell decisions are like driving on a motorway

A key discovery in the new research is how the cells decide whether to become one type of cell or another.

There are three different hypothetical scenarios.

• The cells are preprogrammed to develop into certain types of cells.

• The cells have to decide to go in one direction of many, and each of these directions opens up new opportunities to further specialize in the direction of one type of cell or another.

• The cells have to decide whether to develop into one type of cell, and if a cell does not do this, it has the opportunity to develop into another type of cell.

The new research shows that the cells follow the third option.

”Like driving on a motorway, there is always a new exit that leads somewhere. This is also how the cells develop. Once they have passed an exit, they cannot develop into that type of cell, and then they have to make the choice to become the next type or the one after,” says Maria Eleni Kastriti.

An interesting aspect of this conclusion is that the cells’ first possible decision is whether to develop into neurons in the sensory organs and the last possible option is whether to develop into neurons in the autonomic nervous system that regulates breathing and heart rate, among other involuntary functions.

“Interestingly, a cell’s first and last options are to develop into a neuron, with the decisions on the other types of cells in between,” says Maria Eleni Kastriti.

Studying how cells develop in mouse fetuses

Maria Eleni Kastriti and her colleagues studied gene expression in mouse fetuses.

They used various genetic engineering techniques to measure the activity of various groups of genes on the single-cell level and determined how cells interact genetically in different locations in the bodies of the mice and at different times as the fetus underwent early development.

Based on these observations, they proposed a hypothesis on the options facing neural crest cells as the fetus develops.

Making specialized intestinal cells in the laboratory

The discovery has several interesting perspectives that may become clinically relevant in the future.

For example, some people have such a severe stomach infection that doctors have to remove some of their intestines.

In this situation, the doctors would like to be able to replace the intestinal tissue they removed with new tissue. However, cultivating artificial tissue in the laboratory requires that doctors know how to influence the cell culture environment so the cells can develop into exactly the cells needed to construct a new section of the intestines. Creating a functional enteric nervous system in vitro is especially demanding. This is absolutely necessary for any intestinal transplant to be functional. This research provides important insight into how cells derived from the same patient could be used and reprogrammed to colonize the manufactured tissue, leading to fully functional intestinal transplants.

One can also imagine a similar situation for people with impaired hearing when the specialized neurons inside the ear have been damaged. The damaged tissue can also be replaced, but only if the cells can be induced to develop in the direction of the missing type of cell.

“This also applies to people with certain congenital diseases in which the development of certain types of cells originating from the neural crest cells malfunctions. Our discovery can help to identify where things go wrong and can help shape the direction for developing therapy that might repair the damaged tissue. Neural crest cells are present in the skin, and the cells that are missing can be created from a skin biopsy, but only if you know how to influence them to develop in the right direction,” explains Maria Eleni Kastriti.

Improving knowledge about cancer

Another field in which this discovery may be interesting is improving our understanding of how some types of cancer develop.

The development of some types of cancer, such as paraganglioma or pheochromocytoma, cancer in the body cavity close to the kidneys, involves more than one type of cell.

The evidence suggests that the cancerous event could originate from a time before the cells differentiated, dating back to the stage of the neural crest cells

With the overview of the different stages of cellular development, the researchers can now determine at what point during fetal development any malfunction may have arisen.

“Much research is already being carried out in this field because it will significantly improve understanding of how several types of cancer develop that we do not know much about today and how different types of cancer in the periphery of the body can be so fundamentally heterogeneous,” explains Maria Eleni Kastriti.

”Spatiotemporal structure of cell fate decisions in murine neural crest” has been published in Science. In 2017, the Novo Nordisk Foundation awarded a grant to co-author Maria Eleni Kastriti for the project Profiling of Neuroendocrine Cells and Novel Cell Types in the Human and Mouse Adrenal Gland.