Todd Nystul, University of California at San Francisco
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Stem cells are what repair and replace tissues as mature cells die or are lost. They do it by dividing in two. But how does one daughter cell know to migrate away and become part of the surrounding tissue while the other remains as a stem cell? The answer might be to do just with the shape of the cells. Todd Nystul has found that when epithelial cells divide, the daughter is pushed out of the stem cell layer and then develops a bottom, sides, and a top, unlike its parent which lacks a top. This top might allow the cell to respond to other signals in the local environment, triggering it to move away and specialize.
Todd - One of the ideas in the stem cell field about how these differences could be specified is that stem cells reside in a specialised micro-environment in the tissue that we call a niche. The niche can be made up of other cell types that are nearby. It can be simply be a consequence of the shape of tissue, and the idea is that this external environment provides signals that act on the stem cell and cause it to remain undifferentiated. Whereas, daughter cells move away from that niche and escape those signals, allowing them to go on to differentiate.
Chris - The daughter cell migrates away, escapes the influence of whatever this local factor is, and that releases it to then follow any other local signals or anything intrinsically programmed into it that it inherits from its stem cell parent?
Todd - That’s correct. So, in this case, we were considering the influence of a signal produced by the niche, called EGFR, ligand produced by niche cells and can act on proteins that are present on the surface of the stem cell and then initiate a cascade of events inside the cell. But what is the consequence of activating these proteins on the surface of the cell, and how does that translate to a difference in what makes the stem cell a stem cell versus a daughter, a daughter?
Chris - How did you study that, and in what system?
Todd - We chose to use the fruit fly ovary tissue called the follicle epithelium. Each little unit of the ovary has exactly two epithelial stem cells in them, and we know where the daughter cells that they produced go as they are produced. And so when we look at a tissue, we can really with single cell resolution say, “There’s the stem cell! There’s the daughter that was produced yesterday. There’s one that was produced two days before that,” and ask very precisely what the differences are between them.
Chris - And what did they reveal to you?
Todd - We had started with an observation that the stem cell has a different shape than the daughters that it produces. Epithelial cells in general are known to have a very characteristic shape when they take on their differentiated or functional form, they look very rectangular. They have a bottom and a top, and sides, and each of those surfaces has a different function for the tissue. We noticed that the stem cell had a bottom and it had sides, but no top, and so that made it have more of a triangular shape rather than a rectangle like we would expect from an epithelial cell. That was curious to us because we know that that top is a very important part of the cells functions – the place where the cell can receive signals from the external environment. And so, we started to look into the literature about what was known about signals that regulate cell shape and there was one paper, a little over 20 years ago, that suggested to us that this signalling pathway, the EGFR signalling pathway, could be important. So, we could take out the receptor, specifically from stem cells. When we took it away, the stem cells completely lost their shape and they didn’t have any recognizable shape at all, and nor did their daughters. But if we took it away from the daughter cells, there was no effect at all.
Chris - That’s fascinating on two levels. Because on the one hand, you have something which is controlling the appearance, morphology, of the stem cell itself, but then you’ve got something which appears to direct the behaviour of the daughter cell based on what the parent cell was doing, too.
Todd - Yeah. That was a big surprise for us.
Chris - That daughter cell is out of range because it’s moved away from where this signal must be, to start with. So, there’s something going on downstream of the initial signalling effect, isn’t there?
Todd - Exactly, yeah, and that was a very big surprise for us. Many of the signals that we study which act on a stem cell tend to act just on the stem cell to promote the stem cell identity. But here we had a signal that was not only promoting the stem-like shape of the stem cell, but also by doing so, was setting the stem cell up to produce a daughter cell that would now take on a new shape. And so, one way that we’re thinking about this is that the development of a top to the cell could allow those daughter cells to interact with other cells in the tissue and receive signals from the tissue that tell them to go on to become a functional cell in a tissue. Whereas, stem cells, which lack that top, will not receive those signals and will, therefore, remain undifferentiated in that way.