The Society of Stem Cells

by Arun Mahadevan

The human body, in all its marvelous complexity, develops from a single cell – a fertilized egg. Ponder over that for a minute. The trillions of cells in your body – those in your brain that give rise to your identity, those in your heart that pump blood to the rest of the body, even the cells in the blood itself – all arise from a single cell.

 

How does this remarkable transformation happen?

 

The first cells that arise from the fertilized egg are unique. Over the course of the development of the embryo, these cells multiply and progressively specialize to make up the organs – the brain, heart, skin etc. Fittingly they are called stem cells, as the organism itself ‘stems’ from them.

 

How do stem cells ‘know’ what and how many kinds of cells they should make? Each stem cell contains the genetic blueprint for developing into a human body. However, genes alone do not account for the astonishing complexity of the tissues that are formed from stem cells. The transformation of an irregular mass of stem cells to an organism with unique form and shape relies on a process called self-organization.

 

Self-organization is a phenomenon where large-scale structures like organs and tissues arise from small-scale interactions. The study of these phenomena has traditionally been the domain of physicists, but these concepts are now being applied in biology. A classic example of self-organization in the natural world is the collective behavior of groups of animals, such as a flock of birds. Scientists have found that the behavior of the group can be explained by simple rules that are followed by individual units and how they interact with their closest neighbors.

 

Stem cells show clear features of self-organization, even in artificial lab conditions. When directed to form brain cells, they arrange themselves into structures called neural rosettes, which resemble the tube-like structures in the developing embryo that eventually form the brain and spinal cord. Scientists are increasingly finding that, given just the right conditions, stem cells can self-organize into even more complex tissue-like structures called ‘organoids’ in the lab. (For more information on organoids listen to IndSciComm’s podcast featured in LiveMint)

 

In order to self-organize, stem cells need to communicate with their neighbors, which they do through a variety of methods. They secrete molecules that diffuse into the surroundings and stimulate neighboring cells. Sometimes, they send electrical signals through exchange of ions and even physically tug at their neighbors. Just like groups of friends form networks, stem cells also form social networks through these interactions, which are essential for the development of complex tissues and organs.

 

In my lab, I study how a kind of specialized stem cells called neural stem cells transform into neurons, in a petri dish. I grow the neural stem cells in a broth containing specific chemicals called growth factors that maintain them as stem cells. On withdrawing these chemicals from the broth, the stem cells transform into a highly organized network of neurons over the course of a couple of weeks.

 

This transformation is truly magical, even for scientists. I observe the process through a microscope equipped with a camera to take several images of these cells while they grow and develop. By putting these images together, I then create time-lapse movies like this one.

 

gif1.gif
A 8-day time lapse movie of differentiating stem cells

 

 

Next, I analyze the movies for patterns in the ways that cells arrange themselves on the petri dish. This portion is rather like observing the flight of a flock of birds, trying to understand the rules that govern their collective motion.

graphOverlay_zoom
Computer code detects cells (red outlines) and connects nearby cells (yellow lines)

For this analysis, I use an algorithm to automatically recognize cells and – here’s the interesting bit – draw a hypothetical ‘connection’ between cells that are close to each other. Remember, self-organization occurs through small-scale interactions. If stem cells are close together, they are likely communicating with each other. Connecting nearby cells allows us to model possible interactions between them and how they lead to emergent patterns.

 

 

gif2.gif
The social network of stem cells. Cell outlines are red and nearby cells are connected by yellow lines

 

What kind of information can we get from connecting cells in this manner? You may have heard of the concept called six degrees of separation, the idea that everyone in the world can be connected through a chain of six or fewer friends. Metrics like degrees of separation are commonly used by mathematicians to describe social interactions among people. I adapt many of these metrics to characterize the social interactions among stem cells as they grow into neurons.
Using our cell-network model, we observed that cells are initially well connected to each other. This keeps the degree of separation small. Over time however, as they progressively mature into neuronal networks, the degree of separation increases. This indicates that stem cell communities change from being homogeneous networks of cells to clusters of neurons separated by large physical distances.

 

Why do stem cells and neurons pattern themselves in these different ways? Perhaps the answer lies in differences in patterns of communication. Think of a room of people conversing freely with each other before splitting up into small teams to discuss topics among themselves. Is something similar happening with the stem cells as they develop into neurons?

StemCells_Neurons_graphs
Well-connected stem cell networks (left) and modular neuronal networks (right). In the top
panel, neurons are stained red, astrocytes are stained white and all cell nuclei are stained blue.
In the bottom panel, cell nuclei are outlined in red and nearby nuclei are connected by yellow
lines.

We tested our hypothesis using a technique called calcium imaging. Visualizing the change in calcium concentration in a cell is a way of eavesdropping into cell-cell communication. As messages are passed between cells, there is a temporary increase in the concentration of calcium ions in the cell that receives a message. By using a fluorescent dye that binds to calcium ions and powerful microscopy, this change in calcium can be visualized, allowing us to infer which cells are talking to each other.

 

Calcium imaging experiments showed that stem cell cultures did indeed have greater network-wide communication than neuronal cultures. This confirmed that network-wide signaling in stem cells gave way to more localized signaling in neurons, rather like groups of people breaking up into teams.

 

Why do stem cells and neurons pattern themselves in these ways? The answer could lie in the nature of the tasks that each of these cells need to perform. Many tasks that stem cells need to perform in the developing embryo – sensing chemicals in the environment, migrating to specific regions – are best done as a collective. It makes sense for stem cells to be arranged in such a way that there is widespread communication among the whole population.

 

On the other hand, the clustered arrangements favored by neurons is likely because they form small-world networks. In math parlance, a small-world network is one that has high clustering, but also high connectivity due to ‘shortcut’ connections. Returning to the social network analogy, think of people who have many more friends than the average person, who connect different groups of friends. It is because of these social butterflies that the average degree of separation between any two people in the world is as low as six!

 

Neurons have been known to form small-world networks in the brain and even on dishes, by arranging in clustered modular units and connecting different units through ‘shortcut’ long-range connections. This type of arrangement minimizes the amount of physical wiring needed to connect neurons, wiring that is costly for the cells to maintain. It is likely that this is what we are seeing in our experiments.

 

Studying and modelling biological self-organization of stem cells in a dish has broad significance, besides satisfying the idle curiosity of people like me. Several neurological disorders like schizophrenia, autism and Alzheimer’s occurs due to the neurons in our brains forming aberrant connections, severely disrupting normal brain function. By modeling the way neurons develop from stem cells and form connections in a dish, we can understand more about normal development and how it goes wrong in disease.

 

Additionally, stem cells offer a way to replace damaged tissue in neurological disorders. Stem cell therapies are increasingly being tested in clinical trials and offer a lot of promise in curing once-untreatable disorders like stroke and Parkinson’s disease. Uncovering the secrets behind the remarkable transformation from stem cells to an organism would greatly enhance the chances of success for these therapies.

 

The author is a Graduate Student in Bioengineering at Rice University, Houston, Texas. He tweets at @arun_mahadevan

Link to original scientific article – https://www.biorxiv.org/content/early/2017/08/25/055533

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