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Fantastic Stem Cells and Where to Find Them

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What if we could trick stem cells into thinking they were young again? What would the impact be on human health and aging? Shiri Gur-Cohen, Ph.D., shares her work in this presentation…

Credit: University of California Television

Video Transcript:

[MUSIC] Stem cells holds the power for generation, but stem cells can age. What if I can tell you that we can trick the stem cells, that we can tell them that they’re actually not old, that they’re young. That they can do exactly the same thing that they used to do when they are young which is to regenerate our tissues. I’m Sherry. I’m the new Assistant Professor here in the division of regenerative medicine.

What I’m going to show you today is that it’s not only possible to trick the stem cells, but they may represent the very near future where we can grow old with time, but stay healthy and hopefully happy and satisfied. Let me start by telling you that our body has a remarkable regenerative capacity. Although in humans almost exclusively, if you lose the limb, you lose it forever, it doesn’t mean that you stop growing. In fact, we’re losing in a single day billions of cells. This is completely normal.

The way that I like to think about it is that we all know how he woke up this morning, but we must have changed several times.

At the cellular level, you are not the same person that you woke up this morning. In fact, as we speak, our body is in a constant state of regeneration. Some organs replace themselves very fast, like the intestine or the skin. In fact, your intestine is completely new every few days.

Your skin, you’re getting a whole new skin once a month or so. Some organs replace themselves very slow like the muscles or not even being replaced at all in the adults like the heart. But key players in this regenerative processes you’ve heard are the stem cells that have the capacity to regenerate our tissues to make sure that there is a constant turnover, but also to regenerate the tissue when we need them to act.

When we have wounds, those stem cells need to act very fast, when we’re losing blood, those stem cells need to act immediately to replenish the damaged tissue. I grew up with my grandma and back then I didn’t need to have any stem cell textbook to tell me the tissue regeneration is an arrow with the one negative direction.

We are constantly exposed to damage to the sun UV damage. We’re exposed to pathogens, we’re exposed to wounds. All that really requires our stem cells to work very hard to repair it. But with time, that takes longer and longer. When we’re aging, that doesn’t really happen very efficiently.

But what if I tell you that this is not inevitable? What if I tell you that we can trick the stem cells or tell the stem cells or design the stem cells in a way that they can do exactly the same thing that they used to do when they were young, just as long as possible.

In my laboratory, we’re asking exactly these questions. What is the central cause that maintains stem cells youth potential? But also how we can leverage that knowledge to develop new stem cell based technologies so we can tell those stem cells to do it exactly the same thing that they used to do when they are young.

How do you know that you are aging? There are two main ways to know that. One is if you were born in a different century, then by definition you are aging, excepted. The second way that you know that you are aging is that we’re using our eyes and we’re watching. If you will look around you, you will see people.

Normally, the first thing that you will see is their appearance. Usually, someone’s appearance of the skin and their hair is the first clue that immediately reflect on someone’s age. There is a common belief that aging is associated with a decline of the skin appearance. Appearance, we are not having as firm skin as we used to have. We are losing the pigmentation in our hair, in our skin.

Our wounds are not healing as fast. We sometimes see bread spots on the body or sometimes when older people, you see those patches on their skin because their skin is simply not healing as it used to do. One interesting fact about your skin is that it will age much faster than any organ in your body. The reason for it is because we are exposed to the external very harmful environment. DNA damage that happened through the sun, pathogens and wounds, as I’ve been told you.

This is our external surface that’s supposed to protect us, but it is the surface that exposed to the most harmful conditions.

But how fast do we age? Apparently, when we are babies, our skin completely renew itself once in every two weeks or so. I remember being terrified when I saw a scratch on my baby boy skin, but it was completely gone within a few days, there was nothing left..

When we’re teenagers and then we are actually being terrified with each and every scratch in our body, our skin regenerate itself once a month or so. Closer to my age or so I want to think about it at least is that my skin can regenerate itself one thing every two months or so.

As we grow older and older, that takes more and more time. We see aging all the time. If all of us are lucky, we will age.

We think it’s completely normal. We sometimes even try to do it gracefully. We’re trying to age gracefully. But to me as a stem cell biologist, it really means that there is a problem underneath the surface. It means that your stem cells are no longer able to do what they were designed to do, which is to regenerate your tissues on-demand, exactly the time when they need to work.

When is that actually a problem? It’s a problem when you have wounds and they simply don’t heal themselves anymore. That is chronic wounds. Just to give you a little bit of numbers, but the people in the United States that suffer from chronic wounds exceed the number of people that suffer from breast cancer, lung cancer, and colon cancer combine.

It’s a lot of people.

It’s about three percent of the age population in the world will suffer from chronic wounds. With the increase of age population on earth, the prevalence of chronic wounds rose significantly in the past five years and this is only expected to go up and u because we are making people live longer, but not necessarily healthier. We need to find a better solution. We need to find a better solution for these age stem cells. They need to repair our wounds and they need to do it when we need them to do that job.

We didn’t have this magical powers.

We can’t simply do magic and repair wounds. But we have magical stem cells, and in my view, they’re not less magical from this video and what happened there. Those stem cells can kick in when they need to do, and they will do everything in their power to regenerate your tissues. Where do we find those fantastic stem cells?

Those magical stem cells that reside in your tissues, in most of your tissues, they’re are deep there, down there in the tissue and they normally have the ability to make more of themselves, as Rob was saying. They can self-renew themselves, but they can also create the tissue in which they reside so it means to differentiate.

In the context of the skin, this is the skin that you touch on your body. This is the hair that you see on your head. These are the differentiated cells that create our tissues.

But their fate decisions needs to be balanced because too little of stem selectivity will create insufficient tissue growth like what happened in aging, but too much of it will create cancer. What we really want to understand in stem cell biology, even though I’m working more on the environment and Rob mentioned on the internal thing, we both want to understand what influenced balanced stem cell fate decision. How can we control that stem cells will create the right cell type at the right place, but also at the right time when tissue regeneration needs to happen. I’m stem cell biologist in training but I’m microscopist in my soul, and in my laboratory we are watching. We are watching regeneration when it happens.

We’re watching when stem cells proliferate, when they differentiate, when they migrate, when they are talking with their environment because for us when we capture that moment when stem cells makes their tissue, then we can harness that knowledge to develop new technologies for tissue regeneration while avoiding the risk for malignant transformation. To watch we’re using the microscope and the skin is very unique because it’s a home for multiple types of stem cells. It’s a home for the epidermal stem cells that will create our skin.

It’s a home for the melanocytes stem cells that will create our color; the color of our skin, the color of our hair. It’s also the home for beautiful other organ that’s called the hair follicle.

There we have hair follicle stem cells, and they’re also very unique because at the base of each of your hair follicles we have stem cells here in red. Those stem cells will create a progeny that will fuel the growth of the hair, but why do I think that they’re very magical? Because when you have wounds, those stem cells have the capacity to change their fate. They were designed or evolved during development to create hair, but when you have wounds those stem cells will cross the bridge, cross lineage boundaries, and we’ll create skin. Stem cells will do everything in their power and this is why I was saying, I truly believe that they are magical because they can change their fate in order to regenerate our tissues.

When we think about these stem cells, they are at the base of our hair follicles and they normally act in cycles. Those stem cells normally will be in their resting phase and then at one point, they will become activated and create progeny. This progeny will fuel the growth of the hair. Those progeny eventually will die, leaving only the stem cells to survive to the next cycle. This is exactly what you see all the time our hair grow and shed.

Apparently when you’re younger your stem cells spend half of their time when they’re growing, and half of the time when they’re resting. As we age, the time that they spend in the growth phase dramatically decline. Why is that happening? Why are they becoming dry? Why they’re not doing what they were supposed to be doing.

Because in my view even the driest of seeds, if you will put it in the right environment, if you will put at the right soil with the right conditions with sun and humidity, it will grow.

What the stem cells need when they’re aging, that can really make them grow and flourish. Those environments’ what we call the niches, can also age. What happened to this environment where stem cells reside in? One interesting fact about your hair is the hair growth is sensitive to systemic changes.

We talked about aging, how it is important for stem cells to act when they are during aging but we also know the hormonal cues. When we’re pregnant, our hair is beautiful. The [inaudible] that we gave birth, it’s all going away. We mentioned stress. Stress is also one other thing that we know that affect our hair growth.

Systemic changes that run through our body really affect how our hair grow, and this is just a symbol of how tissue regeneration happens. That really gives me a hint, what might run through our body that potentiate the system to give those cues for the stem cells? To understand that we need to go back to the embryonic state because two systems were born; two very different systems were born, but they became bond for life, the skin and the vascular system.

When one’s senses the heat, the other one will blush. When one senses the breach of its walls, the other one will bring in lots of immune cells and clear the wastes in order to restore tissue integrity.

We have no system that run through our body and potentiate it maybe to be important for stem cells as well. Normally when I talk with people about the vascular system; and apparently I do have the tendency to do that, people normally think about the blood vessels and it’s true we do have blood vessels in our body. These blood circulatory system are important to transfer blood cells and immune cells into our tissues, but we have one more circulatory system and this is the lymphatic vascular system that kept mentioned.

This lymphatic vascular system is important to drain back all the fluids and macromolecules from our tissues back into the circulatory system and to the lymph node that exist in our body. Now I can really ask the question, can the vascular system coordinate the regenerative process and maintain the youth potential of those stem cells that we were talking about?

But by asking that question, I understood that I need a new perspective. Because thinking about the vascular system, it has a three-dimensional view. If you look at this video for example, you may be wrong that the balls are actually going on one-dimension.

You’re completely missing the fact that they’re going up and down. It’s very similar because biology was very much restricted to look at biological phenomena with very thin sections of tissues.

I need a different perspective, but I have a problem because our skin is not transparent. I can simply take it to the microscope and say, okay, how the vascular system look like. It’s almost as if you are taking your camera and taking pictures under the water, you see everything very blurry you. Can appreciate the structure and the colors. What we did, we cleared the thickness of the skin making it completely transparent.

Now I can take my camera in the microscope. When I took all the water droplets outside of the tissue and I can visualize the beautiful architecture of the vascular system around the stem cells without compromising tissue integrity.

This is exactly what we were doing. For the first time we were able to see the beautiful structure of the blood vessels and the lymphatic system in the skin, and we could use to see it also in three-dimension. What we were able to see for the first time; in green you can see the stem cells and in red you can see the lymphatic capillaries, and what we were able to see is that the stem cells are tightly associated with the lymphatic capillaries.

We could model that interaction. You can really appreciate how close they are together. They’re really nesting on top of each other. The stem cells love to be together with their lymphatic vascular system when they’re at the resting phase. Now we’re going to take a virtual tour is if we have a special glasses that allows us to dive into our skin.

What you see in green are the stem cells, in red are the blood vessels, and in white you can see our lymphatic vascular system. Now we’re going to take this virtual tour into our skin. What we found is that the lymphatic capillaries create protrusions that emerge from them and hold the stem cells tight when the stem cells are young and in the resting state, so you can see it also here. Essentially what we found is that the communication between stem cells and lymphatics is controlled by the stem cells themselves. The stem cells have the brain to control how their environment will look like.

They will secrete factors to control the association with lymphatics when they’re at the resting phase. As soon as they will become activated, they will switch to a different program to tell the lymphatics to stay away for a little bit allowing tissue regeneration to happen. This is what happened throughout this cycle, so it’s important for the stem cells to control how lymphatic behavior will look like. The environment is important to maintain balanced stem cell for a decision, but the question remain why hair loss happens when we age? Are we losing the stem cells?

Are they just gone and not growing hair anymore? Or are we losing the soil that the environment, the niche that support the stem cells themselves? What are we losing when stem cells age? This is a very complex question to ask because our tissues are composed of so many stem cells, so many cell types, so many cues and signals.

Imagine we have a pile of LEGO that composes so many colors, and shapes, and types.

How do I find now my stem cells? I ask, what is the difference between young steps? There’s an old stem cells. We live in a very exciting times when science can really push the limits and we can really sort those cells. We can look at them, we can identify the stem cells, and look at their genome and what they express.

To ask what are the differences that a young stem cells do and that old stem cells do. This is exactly what we were doing, but the only thing that I want you to take from this LEGO pile is that the age stem cells and the young stem cells are very similar. They maybe have some different in numbers, but they’re still there. Most importantly, they express exactly the same genes that we would expect them to express when they’re young. All the identity genes that are important for them to know that they are stem cells are still there and they’re almost identical.

Clearly, they are not doing their job right, so they’re not growing hair. You can look at this young mice how they’re going beautiful hair and beautiful fur, but the age mice fail to do that. They are bolded. Their hair simply don’t grow as well as the young mice. They have the stem cells, they express exactly the same identity genes of the young one but they fail to do their jobs, so why hair loss happens as we age?

Again, turning into the microscope because this is what I do best and we looked through clearing how the stem cells look like.

What we find is that the young stem cells are stored in very beautiful compartments called the bulge, they’re very much constrained to this structure. They have two of them, one from the old cycle, one from the new cycle, and they’re very much constrained in their structure. On the other hand when we looked at the old hair follicle stem cells so again just to tell you they are there they’re not gone even though we’re turning bold or the hair is not growing as well, the stem cells are there but their structure is completely collapsed so they’re no longer maintaining this beautiful structure.

Maybe the environment that maintain that structure is also disrupted.

We looked at the lymphatic vessels and I think it’s very clear that all of you can really appreciate that the healthy young mice had beautiful lymphatics. Very well constrained endothelium. They function the way that they’re supposed to function, to drain back fluids and macromolecules. But the age mice had completely different structure. The lymphatics were no longer beautifully oriented in the skin, they were dilated.

Their function was completely disrupted and deteriorates with time. But what’s really important for us to look at is what is the association between those lymphatics and the age stem cells. What you can see here in yellow are the stem cells. The red are the blood vessels, the blue are the lymphatic capillaries. We could look at this in three-dimensional view.

What we found is that the stem cells, again, they are there, they’re not gone.

They’re highly associated with blood vessels. They’re getting nutrients, but they’re no longer associated with the lymphatic capillaries. The beautiful structure that I showed you, that is important for balanced stem cell fate decision too much or too little is no longer there. One important thing that I want you to know about tissue regeneration is that tissue regeneration is a very complex event.

Great coordination between virus cell type requires to establish tissue integrity. We need so many cell types signaling molecules, the metrics, all of that needs to work together in a very orchestrated way. Like in orchestra, in tissue regeneration, we know the musicians, we know the instruments, we know the notes, we know the music, but we don’t know who is the conductor.

Who is the conductor that really makes sure that all the stem cells will work together with their environment in a synchronized way to make sure that the music that we hear tissue regeneration will happen the way that we’re expected to happen? In other words, how do stem cells regenerate the right cell type at the right place and at the right time because this is what happened when you were young, but it declines when we’re aging.

Skin is again very beautiful model to ask that question because the stem cells in the hair follicles are all very synchronized. Either they are in the resting phase and they are all in the resting phase, or that they’re all growing together at the same time so you can appreciate that the follicles are growing at the same time. It’s a beautiful model to ask who is the conductor in this process. What we found is that when lymphatics are no longer functional, when they’re no longer able to make the association with their stem cells, stem cells no longer synchronized.

You can see some small stem cells here in green and some very big follicle together with them.

When that happen, tissue regeneration doesn’t happen anymore because synchronized behavior that stem cells will work with their environment in a synchronized way is important for repair, and when we have wound so it will restore itself. Those big follicles, some stem even develop hyperplasia, so balanced stem cell fate decision didn’t happen anymore.

What happened to these mice that had dysfunctional lymphatics? What you’re looking right now are basically two identical twins. They were born to the same mom at the same time and at the same place.

One of these mice had genetic mutation that cause its lymphatics not to function as good, not to form those connections that I showed you with the stem cells. What we found is that these mice, even though they were young, they started to lose hair prematurely. They basically express signals or their phenotype was premature aging. We can push aging fast forward, but can we reverse it? This is what we all want to know.

We wanted to know that as well so we did an experiment. Together with my colleague Yejing Ge, what we did is to isolate stem cells from the young mice and from the old mice.

We also isolate the environment where the stem cells reside in, and we isolated from the young and the adult and we mixed and matched to see what’s happened. We put the young stem cells in an old environment, and we took the old stem cells and we put them in a young environment. What we found is that the young stem cells when you put them in an old environment, do not regenerate anymore.

This is not what they’re supposed to do. This is not the environment that they need to grow. On the other hand, the old stem cells, when we put them in the young environment, were tricked. They were tricked to think that they’re actually young and they were able to generate hair when normally they did not regenerate here. They were tricked to think that they’re in a young place and they need to regenerate the tissue right now.

I started to tell you that we have so many tissues in our body and I showed you now one environment that control stem cell fate decisions in the skin. But different tissues work very differently. Some tissues regenerate very slow, like the hair follicles in cycles, and some organs very fast like the intestine every few days, the stem cells there are constantly active. Coming back to the question, can we have one central cause for stem cells’ aging? Can it be that one niche, one environment control two different organs that have completely different usage in a similar way?

Or in a different words, can the lymphatic system renew the stem cells in the skin and in the intestine in a similar way? The short answer is yes.

What we found is that even though we have no system that works very fast, the intestinal stem cells here in green are tightly associated with the lymphatic capillaries. What we found is that this association also in the intestine is important to maintain this balance stem cell fate decision and their usage and how much we’re using from these stem cells is controlled by the lymphatic micro-environment. I showed you now a completely new system for stem cell biology right now in regenerating the hair, in regenerating the intestine.

Other words have shown that although not very stem cell centric, but lymphatics are important for brain function and also for heart regeneration and repair.

The question that we are now interested to ask is if it’s possible to slow aging, and can we reverse it? Because now we have a system in hand that runs through our body and can really control all of the stem cells and all of our tissues in a similar way, maybe. These are exactly the question that we’re asking in the lab and can we learn something from how the stem cells interact with their lymphatic micro-environment to make that arrow looks completely different? Just to show you that we are not completely far away from this day because another work from a very good colleague of mine just showed that by preventing age-associated vascular loss in our body can extend the mammalian lifespan.

Not only extend the life of these animal that had better vascular system, they were much healthier. Maybe we can actually just improve the vascular system that runs through our body, live longer, and live healthier life. That will come also with happiness, hopefully. We’re also asking how we can leverage that knowledge and we’re working to develop new technologies to really restore and to trick those H stem cells to think that they’re young again. When stem cells lose its function, we age or we develop diseases and so the ability of stem cells to maintain and repair organs diminish with age.

But paradoxically, at the same time, the risk of cancer increases. That all comes together to the vascular theory of aging because maybe the fountain of youth is actually within us. It runs through our body and as we grow old these pipes are just drying out. Maybe we can restore them or maybe just prevent them from drying out and restore our ability to regenerate our tissues for as long as possible. We may not live forever but I’m one of those that believe that signs can really push the boundaries and we are not that far away from the day that we can actually achieve that.

In my laboratory really study how the epithelial stem cells communicate with their environment, with their supporting niches to understand dynamic tissue in modeling and how we can leverage that knowledge and develop new technologies. With that, I would just like to thank my mentors, my colleagues, my funding resources, and as Rob just said, I will be more than happy just to talk more on not only how to improve the texture of your skin, but really to regenerate our tissues. Thank you so much for being here today virtually and in person. Thank you so much. [APPLAUSE] [MUSIC].

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