A Cell’s Search for Identity

All of us have gone through the torment of high school—the growing pains and the mood swings and the cliques. It turns out that during development the cells of your body also go through something similar to high school. Once a new cell is created in the developing embryo, the cell undergoes a process called cellular differentiation, where it responds to varying cues to choose what kind of cell it’s going to be, or rather how it should respond to the incessant “what do you want to be when you grow up” question. The process of cellular differentiation in embryonic development is very similar to school—the cell enters the process naïve and innocent about the world, and leaves with an idea of who and what it wants to be.

A human body is composed of over 37 trillion cells! All of these trillions of cells come from a single cell, the fertilized egg cell, which then undergoes development to become a fully functioning organism. There are many different types of cells that are necessary to make a functional organism. In the human body, you need about 200 different cell types. You need neural cells to make up the brain and the nervous system, glial cells to aid in “helping” the neural cells. You need skin cells and intestinal cells and muscle cells, among many others, and all of these different cell types have vastly different cell structures, gene expression, and interactions with neighboring cells. How do all these cells choose which cell type they will be and grow up properly into this role?

Examples of many different cell types a stem cell can make; image from blueringmedia/123RF

In the beginning of development, all cells are stem cells, with varying levels of restriction. A cell that is restricted to certain fates has already downregulated genes necessary for those certain fates, be it a single blood cell type or the entire suite of cells necessary to make the skeleton. Cells are created through the division of a parent cell into two daughter cells. In the embryo, daughter cells are naïve stem cells and have the potential to become most cell types. It’s sort of like a newborn baby—you have no idea what this new child is going to do or become. 

However, just like with humans, the potential of a new cell begins with its parents. The location of the parent cell plays a major role in determining what their child will become. 

Think of a limb, like your arm or your leg. There are only so many cell types that are needed by a limb, things like cartilage and bone, skin and muscle, and nerves to give the limb feeling. If a parent cell is located within a developing limb, it has likely aligned its gene expression to what is needed in the limb. The cell has also probably stopped expressing genes that are certainly not needed, like genes that are important for intestinal cells or for the eye. 

These changes in genetic expression, or restrictions, are passed on from parent to daughter cell. This means that the daughter cells of a parent cell in the developing limb do not express genes for, say, intestinal cells. And this makes sense, because you don’t want or need intestinal cells in your arm. However, the daughter cell is still restricted to the cell types that are within the limb, all before the cell has been “born”. 

This image gives a more detailed view of cellular differentiation. A totipotent stem cell is able to give rise to all the cell types of the embryo, but as the embryo begins to develop the number of derivatives, or its potency, become more and more restricted. If a cell of the mesodermal line, for instance, divides, that daughter cell is sealed to a mesodermal fate, and cannot become cell types associated with the endoderm or the ectoderm. image from https://opentextbc.ca/anatomyandphysiology/chapter/3-6-cellular-differentiation/

From there, the daughter cell defines its identity through trial and error, and through interacting with its surroundings. 

Which takes us back to that high school analogy. 

When a cell enters the process of cellular differentiation, it is already predisposed to a certain fate. This fate was influenced by the gene expression of the parent cell and the location in the embryo that the cell was born into. It’s sort of like kids entering school. Their aspirations for the kind of person they want to be is largely influenced at this point by their parents. If a kid’s parent was a doctor, it is very likely that she will also want to pursue something similar. 

The next part of a cell’s journey is highly influenced by its interactions with its environment and with other cells. In other words, the cell is influenced by who it hangs out with and which groups it joins.

Environmental cues are integral for cells in their pathway to identity. The levels of various secreted proteins, small molecules, and things as basic as temperature and oxygen levels have huge influence on the identity choices of the cell. These environmental factors can be both a result of location within the organism (going back to their parent cell), or a result of the cells that are in proximity. This involves movement of molecules between neighboring cells, as well as direct contact and interaction. 

A classic example is that of morphogens during fruit fly development. A morphogen is a secreted molecule that forms a gradient of different concentrations, and is able to influence the differentiation of a cell depending on its concentration. In fruit flies, the mother deposits the morphogen bicoid at one end of the embryo. During early fruit fly development, bicoid then diffuses throughout the primitive embryo, creating a gradient. This gradient is important, because it turns out that the part of the embryo with high bicoid protein becomes the head of the fruit fly, whereas the area with low bicoid levels will become the tail. Messing with bicoid levels messes with the entirety of the embryo, sometimes creating embryos that have two heads or two tails!

Example of a morphogen. image from https://dev.biologists.org/content/131/23/5897

Cells become more restricted in their differentiation through regulating their gene expression. A neural and an intestinal cell have the exact same genetic content, the only difference between the two is which genes are active. In the previous example, cells that had a lot of bicoid began expressing genes that were specific for development of the head, and cells that had less bicoid began expressing genes that were specific for the tail. 

It’s sort of like cliques in high school. You’ve got the preps, the nerds, the theatre kids, the jocks, you name it. Each student going into school has a predisposition. They have different goals based on their parents, and different skills and talents based on what they’ve been exposed to. Usually, this means that they will gravitate towards the people who are more similar to them. The kid that wants to be a doctor will likely join academic clubs and hang out with other high achieving classmates. These interactions, and the studious environment caused by being surrounded by other high achievers will reinforce the same habits in that kid. It’s the same for cells. 

Of course, there are always cases where identities change drastically in response to interactions. A kid who was brought up by academic parents suddenly decides to abandon studying and join the skaters because all their friends are skaters. This happens with cells as well. Sometimes a small group of cells suddenly changes their genetic expression to become something radically different than their parents. In most cases, this is okay. It’s the means by which new tissues and organs are formed during development, for instance, and is actually called asymmetric cell division. However, sometimes it’s not okay, like when an adult suddenly has some lung cells that decide they are done being lung cells, and become cancerous instead. 

The analogy of cells to high schoolers isn’t necessarily exact. Cells, for instance, don’t go through a rebellious phase where they try on many different identities because that would be disastrous for the organism. And high school students are exposed to a huge array of options during their schooling, giving them many more options than cells, which are generally more restricted by the location of their parent cell than kids are by their own parents. 

Still, the nature and nurture of both is similar. Both cells and high schoolers are heavily influenced by both intrinsic and extrinsic factors as they grow and develop. Their goals are also the same. Once a cell exits cell differentiation they are now a determined cell, restricted to a particular fate. High school students who graduate leave with a better understanding of their identities and what they want to be in the world. 

No matter how good or bad your high school experience, it is undeniable that it played a large role in your life and finding your identity. It’s amazing to think that these same principles can be applied to the trillions of cells that make up our bodies.