AudioHelicase Special: Rebuilding a Body

This story is part of our series, Cells Over Time. Click here to see all stories in this collection. 

In this special episode of AudioHelicase, we talk to three researchers about the cells in our bodies that can regenerate – and those that can’t. We ask, why can some cells no longer renew themselves? And, importantly, can we change that?

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Edited Transcript: 

Iain Cheeseman: We have about 30 trillion cells in our body. Today, about 50 billion cells in my body are going to divide. That's a lot of cell divisions. But the vast, vast, vast majority of cells are not going to be dividing today. Many of those probably wouldn't ever be able to do it again. They've entered a state where they're not competent to ever be able to undergo another division.

Eva Frederick: That’s Iain Cheeseman, a Whitehead Institute Member and professor of biology at the Massachusetts Institute of Technology. His research is helping to reveal what is going on with cells that aren’t dividing anymore. In some cases, those cells can be a limiting factor on how well your body can function. They might be in your heart, or your brain, or your pancreas. Wherever they are, they’re the only ones you’ve got. 

Frederick: Welcome to AudioHelicase, the podcast of Whitehead Institute, unwinding the science and the people behind some of the Institute’s most exciting discoveries. I’m Eva Frederick, a science writer at Whitehead Institute, and in this special episode of AudioHelicase, we will be talking about those cells that no longer divide. What does this mean for our bodies? Why can they no longer renew themselves? And, importantly, can we change that?

Frederick: Kristin Knouse is a Whitehead Fellow who studies regeneration. I asked her to talk me through what is going on with those non-dividing cells.

Knouse: If you think about the tissues in our body, they tend to fall into two categories. On one hand, we have tissues that are constantly renewing like our intestine, our skin. If you think about if you get a stomach bug, or you cut yourself, you heal in a matter of days, and there's no lasting repercussions from that injury. 

Frederick: These tissues have a secret weapon in regeneration: an ever-present supply of unspecialized cells called stem cells. In addition to renewing themselves, stem cells can divide into a wide range of other cell types. 

Knouse: So anytime there's, you know, a basal level of injury, or an even more extreme injury, those stem cells can rapidly divide, make a new functional cell, and the tissue is back to normal. And so that is true for things like the intestine and skin.

Knouse: Then on the flip side of that are these other tissues that are kind of quite the opposite, they have no normal turnover or means of healing from injury. And so tissues like this include the heart, the brain, the pancreas, and the reason that they can't renew is because they have those specialized functional cells, but they don't have stem cells.

Frederick: These tissues are composed entirely of what scientists call “terminally differentiated” cells. Having reached their full potential as a specialized cell, they permanently exit the cell cyclego into a state of cellular rest called quiescence. That means they no longer take part in the same cycle of DNA replication and division that carries dividing cells through generations. 

Frederick: These are the cells Iain Cheeseman mentioned that are no longer renewing. Without stem cells to refresh their populations periodically, you’re pretty much stuck with the cells you’ve got. 

Frederick: Consider the muscle cells in your heart, called cardiomyocytes. You have the same heart muscle cells you had as a baby, and will carry those same cells with you until you die. That’s one reason why conditions that cause damage to the heart or brain can be so serious. Unable to heal themselves, the tissues slowly succumb to the accumulated damage. 

Frederick: But what if, somehow, we could induce these cells to dig deep into their genetic memory, and regain that regenerative capacity? 

Knouse: “It would be incredibly powerful if we could convince those terminally differentiated cells, the cardiomyocytes or the neurons, to go back into the cell cycle and sort of behave somewhat like a stem cell to heal the tissue when needed. 

Frederick: This idea — a therapy that could convince part of a human body like a heart or a brain to regrow — is a basic principle of regenerative medicine. On its face, it might sound like science fiction. But think about it; every cell is the body is the product of a cell division. An individual cell might change over time to be specially adapted for its task in the body, and lose the capacity to regenerate. But that cell still carries the same DNA in its nucleus, the same instructions that any stem cell uses.  

Knouse: The genome, the book that these two cells are reading, is the same, it's a question of what sentence so they're actually listening to. 

Frederick: If scientists can identify which genes need to be turned on for a cell to reenter a dividing phase, it could open the door for new therapies to regrow damaged tissues.

Knouse: We sort of have in our heads this distinction of stem cells can divide, differentiated cells can't. 

Frederick: But this doesn’t have to be true — and in some cases it isn’t.

Knouse: The liver really emerges as an incredibly unique and informative exception, because it has the ability to regenerate itself after an extreme injury. You can cut off 75% of the liver, and it completely regenerates. And importantly, there are no stem cells in the liver.

Frederick: The liver is made of just, well, liver cells. These cells, called hepatocytes, rest in quiescence until distrubed. Then, they have the ability to re-enter the cell cycle when they need to.

 Knouse: What that tells us is that a cell cycle arrest is not an obligate consequence of differentiation. You can be a differentiated hepatocyte, and retain the ability to go into the cell cycle. And so in principle, the ability for an organ to regenerate need not require a stem cell population. 

Frederick: That’s where Cheeseman’s work comes in. His lab focuses on the cellular machinery needed for division, and one of his postdocs had been studying tissues in quiescence for clues about how these cells retained the ability to divide, even after years of rest. 

Cheeseman: I think we basically just assumed that was sort of the boring part of the cell cycle  that nothing is really happening there. But recent work in this particular work from postdoc Zak Swartz in our lab has said that that's actually not occurring.

Frederick:  Like the liver cells in Knouse’s lab, the “resting” cells Swartz studied — specifically, starfish egg cells — were able to spend most of the animal’s life in a nondividing state, and then leap back into the cell cycle at the appropriate time.

Frederick: When Cheeseman and Swartz investigated what cellular components made this possible, they zeroed in on a particular protein called CENP-A. CENP-A is part of the machinery that allows cells to successfully divide. 

Cheeseman: The idea was that it just basically was rock solid, stable and doesn't turn over.

Frederick: Upon closer inspection, though, the researchers noticed a slow, nearly imperceptible change in the CENP-A levels in resting cells.

Cheeseman: What we see across these different conditions is that it actually is being turned over and is constantly being reincorporated, but it's just happening at such a low rate that we didn't really notice that. And so it's about maybe 5% per day. 

Frederick: 5% per day is not a lot when you're dividing every 24 hours. But if you're sitting static for a couple weeks, that becomes pretty important. 

Frederick: This held true across a number of different tissues, including starfish and human egg cells, or oocytes, and quiescent cell lines.  Swartz noticed that in all these cells that retained the ability to divide, CENP-A was being constantly refreshed.

Frederick: When they looked at terminally differentiated muscle cells, however, there were much lower amounts of CENP-A at their centromeres. That means that CENP-A is one of those genes Knouse mentioned earlier — a page of the genetic book that terminally differentiated cells were somehow skipping over. 

Frederick: Of course, starfish eggs and human livers are not comparable in many respects.

Cheeseman: The system is very different, the organisms are different, the situations are different, but we see a very similar thing, which is that if you're ever going to be able to divide again, you have to think about preserving the cell division machinery in your proliferative potential. 

Frederick: This finding led Cheeseman’s research in a new direction, focusing not only on quiescent tissues, but also on tissues that have been damaged by the ravages of time.

Cheeseman: This has opened a new door for us in terms of thinking about the absence of division as being a really important thing for us to study. And then also really how these change during aging, and, you know, our bodies changed dramatically and a lot of ways as, as we age, and this connection between the ability to divide and proliferate and repair and replenish tissues and what changes in the bodies of ages is something I think we're really curious to investigate.

Frederick: So far we’ve talked about the cells in the human body that are no longer able to divide. And while there are promising advances in the field of regenerative medicine, we are nowhere close to being able to regrow a missing arm or leg. 

Frederick: Humans aren’t actually that good at regenerating, all things considered. That’s one reason Peter Reddien, a Whitehead Institute Member and professor of biology at MIT, is looking to our regenerative superiors to see if we can learn a thing or two from their expertise. Just who are these regenerative superstars? 

Reddien: Planarians are cross-eyed, small, aquatic invertebrates. They range in size from a couple of millimeters to a couple of centimeters. They're found in freshwater bodies all over the world. And they are famous for their abilities to regenerate. 

Frederick: Chop one of these slimy, tic-tac-sized worms into pieces, and each piece will regrow, in a few weeks, into a fully-formed worm. The worms are able to do this thanks to a population of cells called neoblasts.

Reddien: Neoblasts are definitely a special cell type in the animal kingdom. They are amazing cells. They exist continuously into adulthood in planarians. And they are found throughout the body. 

Frederick: Kind of like human stem cells, neoblasts are constantly active, constantly dividing, in order to preserve their own populations and replenish the worms’ other tissues. 

Reddien: Following injury, these cells are capable of making everything. They can make every differentiated cell type of the animal.

Frederick: So it’s no surprise, given these amazing cells, that planarians are a bit better than us at regenerating. But let’s go back to what we mentioned earlier, about cutting a worm into pieces. That’s not just a normal wound — that means the planarian has to regrow the majority of its little body. More of the planarian is gone than is left over. And that sort of large-scale regeneration requires more than just a few special cells. In order to regrow a body, Reddien and his colleagues knew there must be some larger patterning at work in the worms, telling those neoblasts where to go and what to become.

Reddien: Unexpectedly, we found that muscle cells have an instructive role in regeneration. 

Reddien: These muscle cells are acting like the satellites in a global positioning system, sort of a coordinate system of instructions that tell cells where they are. 

Reddien: Just imagine, for example, let's say a region of the tail of a planarian, and that's going to regenerate its head. So at time zero after a tail has been amputated, the muscle cells express the tail positional information, and then at later time points at the wound side, the previously tail muscle cells or new muscle coming from previously tail stem cells have to start expressing head instructions. And so we watch this process and snapshots happening dynamically within the muscle. We think this, this process of resetting instructions about position is guiding regeneration. And so we're very interested in the steps how it happens, the genes that are involved in bringing this change about.

Frederick: So in his work, Reddien tracks planarian stem cells (the neoblasts) and planarian muscle cells. 

Reddien: There is a third category of processes in which we are tracking cells that are important for regeneration. And, in this category, we're tracking how cells make migratory choices. So stem cells that make fate choices, let's say to make an eye cell or a skin cell, make those fate choices far from where they need to be. And so when they finally will specialize and differentiate into their final target cell type. And so we were tracking how these stem cells know where to go. 

Reddien: And we found that these cells are following some, some cell extrinsic cues to find where they should go in the body. And so they're migrating and sorting themselves out to do this. And they also make choices based on which cells they bump into and interact with. So if a cell that has become a progenitor, let's say, for an eye, bumps into an eye, an existing eye, then it gets sucked into that eye, even if that is in the wrong location. 

Frederick: (This line of experiments led to a few planarians in the Reddien lab sporting three or more eyes.) 

Reddien: We think this is a driver of tissue pattern, the interactions of progenitor cells with their target tissue. And so we're tracking cells as they're making these migratory decisions.

Frederick: Reddien’s research continues to reveal how regeneration happens, on a whole-organism scale. 

Cheeseman: I love that connection between what our lab cares about what Peter's lab cares about. 

Frederick: That’s Iain Cheeseman again.

Cheeseman: I think that we typically care about what's inside itself, and how you're building these machines and players to be able to have them enable those, those processes. Peter’s lab really cares about that organismal scale and the relationships between individual cells and the patterning on an organismal level.

Frederick: Taken together, Cheeseman’s, Reddien’s and Knouse’s work tackle the mysteries of regeneration from a number of angles. 

Knouse: Certainly my personal moonshot as a scientist would be that one day, if someone has a heart attack or stroke, we can administer some sort of therapy that convinces the neighboring cells adjacent to that injury to reenter the cell cycle, fill the wound and fully restore tissue function. 

Frederick: That’s all for this episode. Thanks for listening. You can learn more about research on regeneration at Whitehead Institute on our website at wi.mit.edu. This episode of AudioHelicase is part of our multimedia series called “Tracking Cells Through Time.” You can find other parts of this series on our website as well. 

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