What are stem cells, and how do changes in their metabolism drive differentiation?
[Writer] This is Sharon Parmet with research news from UIC, the University of Illinois at Chicago. I spoke with Dr. Jalees Rehman, associate professor of medicine and pharmacology in the UIC College of Medicine, about stem cells and how his recent research on changes in metabolism in stem cells as they begin to differentiate may give scientists an edge when it comes to producing more and more functional mature cells from stem cells in the lab.
Dr. Rehman, can you tell me what exactly is a stem cell and how is it different from say, a skin cell or neuron?
[Rehman] A stem cell is a cell that has not yet chosen its ultimate fate. A stem cell has the potential of becoming a variety of different cell types such as a cardiac cell, or a neuron. Mature cells, like cardiac cells, cardiomyocytes or neurons, are stuck in that cell fate – its very hard to move them out of that fate and convert them to another kind of cell type. This is what makes stem cells so attractive for regenerative medicine. You can take a cell – a stem cell – expand it, so out of a single cell you can make millions of cells, and then use them to build new tissues, new organs, and regenerate diseased tissue.
[Writer] How do scientists make mature cells from embryonic stem cells in the lab?
[Rehman] Our goal is to make mature cells that are able to function like healthy cells you would find in the body. So if we want to make a cardiomyocyte, we want the stem cell to turn into a cardiomyocyte that can contract, that can beat, that can conduct electrical signals just like a regular adult healthy human cardiac cell. In order to do that, we try to learn from development. Embryos grow in a uterus, and their stem cells are given – provided – cues by the developing organism which tells certain stem cells to become brain cells, neurons, others become cardiomyocytes, some stem cells turn into muscle cells. This is a very complex and coordinated array of commands that are ultimately processed in every individual cell. What we have done – many of the scientists that work in this field – we have learned from that process by studying stem cells in a variety of organisms, such as mice, we then try to mimic that process in a petri dish. So we add chemicals, growth factors, other environmental cues to help along the stem cells and sort of instruct them to choose a cell fate and mature into the cell type that we then need for our experiments and hopefully ultimately one day to help regenerate diseased tissue.
[Writer] Much of your research focuses on how stem cells become endothelial cells- the cells that make up blood vessels. Why would scientists want to make blood vessel cells from human stem cells? What is the problem with using blood vessels from cadaver donors to treat cardiac disease?
[Rehman] The first answer to this is supply and demand. We don’t have enough cadavers available to donate the blood vessels that we need. As you know, cardiovascular disease is one of the leading causes of disease, and death, unfortunately, in the world, and there are literally millions and millions of people suffering from cardiovascular disease and have blockages in their blood vessels, their blood vessels are not able to dilate enough to let the blood perfuse – the blood flow is not enough to get into the different organs. And with diabetes, obesity increasing, cardiovascular disease might even get worse. So if we want to regenerate blood vessels, help them become healthy or even build bypass blood vessels, we definitely need more building blocks, and stem cells are a great choice to build blood vessels. The second thing is that when we make blood vessels in our lab from stem cells they are fresh. They haven’t suffered through all the injuries or damages that a blood vessel suffers from in a person who ultimately becomes a donor. When we get a donor blood vessel, it’s very hard to know whether that donor blood vessel is going to be healthy or not. Right now, we do our best to estimate how healthy the blood vessels are. But if we were able to generate really healthy, functional blood vessels in the lab, we could do quality control checks on these blood vessels before we implant them in patients or before we use them to build new organs. And I think the last important point is that with the new technology we can generate fresh stem cells from a skin cell off a patient. We can actually build blood vessels that genetically match the patient who needs them. And I think that’s one of the most exciting developments in stem cell biology is to use the so-called induced pluripotent stem cells – IPSCs – which will ultimately lead to personalized regenerative medicine.
[Writer] It’s clear that making blood vessels from stem cells has significant therapeutic potential for treating heart disease. Can you tell me what your most recent research, published in Cell Reports, says about how changes in stem cell metabolism could play a major role in the differentiation of stem cells?
[Rehman] As I mentioned before, there are many ways to convert a stem cell to a mature cell like a neuron, or in our case, a blood vessel cell and most of the methods that are used to help stem cells choose their ultimate fate have relied on chemicals and growth factors and other proteins that are added. But what we thought is that the metabolic environment of a stem cell changes as it matures. For example, a cardiac cell has to continuously beat and conduct electrical signals. It has a completely different metabolic environment – very heavy on generating a lot of energy, using up carbohydrates and fat to keep going, from a stem cell, which does not contract at all, and we extended that idea to blood vessel endothelial cells and we analyzed: is it possible that for a stem cell to become a successfully functional blood vessel cell, you also have to take into account that its metabolic environment will change.
So we did a metabolic analysis of stem cells and blood vessel cells that are mature, and found that there was one amino acid – glutamine – which is really important for stem cells, and it is metabolized to a lesser degree by mature blood vessel endothelial cells. And we then asked the question: is it just that blood vessel cells don’t need glutamine or is the shift in metabolism actually necessary for it to become a mature blood vessel cell and when we changed the glutamine metabolism, we suppressed the glutamine metabolism of the stem cell, we found not only did the cells — the stem cells — increasingly become endothelial cells, they even became better blood vessel cells. They became able to migrate better, form better blood vessels, and we think that this is a really important concept in stem cell biology that you can make highly functional, effective mature cells if you take their shift in metabolism into account.
[Writer] Dr. Jalees Rehman is associate professor of medicine and pharmacology in the UIC College of Medicine. This has been research news from UIC, the University of Illinois at Chicago. For more information on UIC visit www.uic.edu