Artificial organ research Reported August 27, 2007

Growing Blood Vessels -- In Depth Doctor's Interview

Nelson Fausto, M.D., tells us about progress in the field of artificial organ research. He and his colleagues are working on growing livers in a lab.

Ivanhoe Broadcast Interview with

Nelson Fausto, M.D., Pathologist

University of Washington

Seattle, WA

TOPIC: Growing Body Parts

Date of Interview: May, 2007

You and your team started this research about three years ago. Can you give me just a brief explanation of what you are doing?

Dr. Fausto: We are very much interested in looking for stem cells in the human liver. So we decided to start working with fetal livers, because we felt that if, indeed, we could find stem cells, it would be easier to find in the fetal liver rather than the adult liver, although those cells may be present in the adult liver. So, we began to look for special kinds of cells in the fetal liver. We obtain the fetal liver -- fetal material is donated for research and is given to the University of Washington. We begin to establish cultures of livers of fetuses in the first trimester of pregnancy. We get a small fragment of the liver and then dissociate or separate the cells from those livers. We were looking for cells that have characteristics that are not the ones that we are normally used to seeing in the liver. After a very long period of time -- more than a year -- we found a type of cell that perhaps could have been considered a stem cell, so then we went from there. I think the goal of the research is really two-fold. One is really science, the other one is really the practical application. The science here is to find out exactly how the liver is really built up and how many cells it has and what types of cells it has. The practical applications are pretty obvious, right? If we find the cell that is a stem cell for the liver, the idea is that we can then, perhaps, inject those cells and repopulate livers that have been injured, particularly after acute injury when there is major destruction of liver cells. So, we had this dual goal in looking for those cells.

Why is it important to find a way to regenerate damaged liver cells?

Dr. Fausto: The liver is a very interesting organ because the adult liver is one of the only organs that have this unique capacity to regenerate. But obviously it doesn't work all the time, and it very often fails. That's when you have chronic disease or the most obvious things are the acute liver failure in which there is massive cell death because of viruses or a toxin and so on in which you need to replenish the liver cell population rather quickly. At this point, there is really nothing that can be done. The physician is basically expected to just keep the patient alive until he can go for transplantation. The idea is that if you could have cells that could be introduced into the patient, it could either be a permanent solution for that or at least serve as a bridge until a transplantation can be done.

What have you found so far in the mice you have been experimenting with?

Dr. Fausto: We worked with mice for many, many years, and then we decided to look into humans and say, 'Would humans have those kinds of cells?' The liver has two different types of lineages; one are the main cells, called hepatocytes; and the other ones are the cells that produce bile. Those cells are called cholangiocytes. So, our criteria for finding those cells were to find cells that, if we put in culture, we could direct them into making hepatocytes or cholangiocytes. We found those kinds of cells, but the big surprise is that by modifying the way we grow those cells, those cells turn out to be able to produce many other different tissues. So they can produce cartilage, they can produce bone, they can produce blood vessels, they can produce fat. So it became more than just a liver stem cell. It became a sort of a stem cell with a very broad property of producing tissues, which, from a biological perspective, is extremely interesting. I find it quite remarkable that with all this enormous amount of research in the liver nobody had really come across those cells beforehand -- including our selves. Clearly in the early development of the liver, there are cells that resemble almost like an embryonic type of stem cell that is past embryonic period but is still present in the liver. Our guess is that those cells exist in the adult liver also, although in very small proportion. So, the real question is what do they do in the adult liver? Do they participate, for instance, in the repopulation in the adult liver? Do they participate in cancer of the liver and so on? But the biological properties of the cells was a real surprise, because we were looking for something that was specific for the liver, and it turns out that those cells have an enormous range of capabilities of producing most tissues that we try. It doesn't produce blood cells and it doesn't nervous tissue.

What else did you find in your research?

Dr. Fausto: Those cells are very interesting because they are almost embryonic stem cells, but this is no longer in the embryonic period. So, that means that during development of those organs and perhaps in the adult liver, there are cells with the capacity of producing a variety of tissues. If they are in the liver, they produce liver cells. But if they go in to bone, they can produce bone; they can produce blood vessels and so on. So, biologically, this is a very interesting finding in terms of the developmental potential of those cells. As we use the cells to repopulate livers it's quite likely that those cells could be used to produce blood vessels. All of this depends on how we grow the cells, how we culture the cells. We have markers for each one of those tissues. So our guess is that in the animal, or in humans, they would show those capabilities regardless of where they are. So, when I said that our research has a dual goal -- one is the biology, the other one is the application -- the biology became extremely interesting in terms of what people talk about the plasticity of the cells and the type of cell that can produce so many different tissues. These are all sort of new discoveries in the last two, three years to find cells that are able to do that.

Do we know how far we are from possibly trying it in humans?

Dr. Fausto: The main difficulties are the immunological reactions against the cells, because you are adding cells from another individual into that person with the injured liver. So, that's the main problem. Would the cells be rejected? The second difficulty is how do you really introduce those cells in the liver? That's less of a difficulty because there are now methods in which you can put the cells through small catheters and even leave the catheters in place. You leave them in place and you can infuse those cells if you have enough. So, it means that you have to have sufficient amounts of cells to do those sorts of transplantations. I think it's years ahead. Not so much because the cells will not grow, but in terms of the rejection. Also, if we are talking about acute situations, you want cells that grow very quickly to serve as bridges or to correct the defect that's acute; otherwise the patient would die. So, all of those things are still to be worked out. Those are really the barriers ahead. It's the same for people working with, for instance, heart repopulation and so on. It's pretty much the same type of problem, but I believe that those things will be overcome. I think the solution is either treating the cells with agents that would prevent them from being too reactive from the point of view of rejection or treating the patient with drugs that would at least prevent the immunological reaction temporarily at least.

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END OF INTERVIEW

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