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2009 Web Conference with Dr. Arturo Alvarez-Buylla 2009 Web Conference with Dr. Arturo Alvarez-Buylla - 00:00 Tell us about yourself and your career and how you started. - 00:06 Well, I actually grew up in Mexico, where I did my undergraduate in a program called biomedical research, and I came to the U.S. to study my PhD at Rockefeller University, where I work with Fernando Nottebohm, studying neurogenesis in canaries and songbirds. And there is where I became very interested in the mechanism of adult neurogenesis, how can cells really get going in a complex environment like the adult brain. And there's a lot of different processes going on from the birth to the migration to then the integration within circuits that are already working, because it's not like the brain has been built. The brain is really put together at a different time, and here the brain is already functional. And circuits that are functional, while not losing function, have to integrate any neurons, and that fascinated me. So that's how we started. Then, I was working off that, I was offered a position at Rockefeller very soon after finishing my PhD at Rockefeller, and I had my first graduate student that came, and he actually told me that he couldn't care less about birds because they were so irrelevant for medicine. He wanted to do something relevant to medicine. And this actually is a very very brilliant student that then went on to do the pioneer work on the migration to the olfactory bulb. He actually, by the way, he's now professor, he has his own lab at MIT, and he's actually now working in birds. See how things go around? I got into stem cells. When we started, the field of stem cells really did not exist. In 1986, while I was still a graduate student at Rockefeller, there was a meeting in Waldorf Astoria where there it was proposed that the fact that this process were going on in the adult brain could open up a whole new field of progenitor studies, and I think that was a little bit one of the places where the stem cell field, at least for the brain, began. But there was very little insight into what it was going to become and how huge. It's more like a fashion now than sometimes real science. So that's a little synopsis of where I came from. And in 2000, I moved from Rockefeller to here, the other side of the continent, to California. And I've been here now nine years at UCSF. 2009 Web Conference with Dr. Arturo Alvarez-Buylla - 02:35 Out of curiosity, how big is your lab now? - We're 11 people. - What? - Postdocs, graduate students, undergraduates. Do you have a full array? - 02:49 Yes, it's right now, this year, three graduate students have graduated. There's actually one graduate student left in the lab, and two that are doing or planning rotations. So the rest of the lab is technicians and postdocs. This is a very interactive institution, so my lab is embedded within the stem cell program. In our floor is David Rowitch, Arnold Kriegstein, and Miguel Ramalho-Santos. We share lab space, we share a lot of equipment, and there's a lot of, also, studies that are in collaboration with a different lab, where postdocs and students are participating in projects that are interdigitated with different programs and different labs. - Okay, so moving on to our questions. Our first one's gonna come from Alexandra. - 03:39 So, could you please summarize for us the structural characteristics of the adult neural stem cell niche and how its organization helps to foster stem cell renewal and neurogenic and gliogenic properties? - 03:55 So how many hours do you have? That's a very deep question. As I mentioned before, when we were working in birds and canaries, we were already excited of how can new neurons be incorporated into a brain that is fully functional? And one of the questions, where these cells are coming from. And even back there, now it's almost 20 years ago, we made the, at the time, relevant observation for mammals because people thought it is was something special for birds that a glial cell was a stem cell. And years later, through work of another graduate student at Fiona Doetsch's lab, we found that also glial cell was acting as primary progenitor in the adult cells that were going to the olfactory bulb, that actually I had mentioned to 2009 Web Conference with Dr. Arturo Alvarez-Buylla you Carlos observed. And that got us very interested in the whole lineage of going from brain ganglion to astrocytes. To the composition-- I guess the first part of your question is how is this niche for neurogenesis organized, and our initial view from the works of Human Touch was that these glial cells that people had identified as astrocytes and we still call them astrocytes, we call them B cells in superventricular zone were actually right under the ependyma and that's why this region is called subventricular zone. Because something happened while they removed from the ventricle. And that D cells divided to generate another cell then, we discovered in the lab, that we call C cell, that's the transient amplifying, does everyone know what a transient amplifying cell is in the lineage? - Yeah. - 05:30 Just let me know if I'm talking in terms that are not understandable. So this transient amplifying cell then turns into the young neurons that go to the olfactory bulb. So if I can draw it here. So, the idea was that there was an ependyma and these cells are very interesting and we can spend time talking about them because they are really fascinating cells and I can tell you more about them. And then right underneath it there was these very complex cell that had processes in between other cells, that we call B cells, and next to them, there were clusters of more rounded cells that are these C cells. So it turned out that D cells that were not simple at all, give rise to the C cells, and then these C cells differentiated into young neurons and these young neurons from chains that migrate to the olfactory bulb. But this four-fold migration was another thing that Carlos Lois discovered in the lab. Chain migration is a way by which cells slip along by each other and migrate very quickly to the olfactory bulb. So the niche has to coordinate and organize three processes, birth, amplification, and actually migration, because migration already happens within the niche. And so you can see that it is quite complex and this was our initial view of how it was organized. The recent work of one of the papers that you read actually suggests that these B cells are not this kind of mushy things that I drew, but actually very interesting cells. The 2009 Web Conference with Dr. Arturo Alvarez-Buylla ependyma cells have little holes through which these B cells project, and then they have other process going back and then these cells have very long basal processes that actually end up in blood vessels. And some of your questions were related to this. So, as you can see, these B cells are much more epithelial than we had originally thought, and how both an apical where there's actually a prime receiver, another structure of great interest to us, and a basal structure and so, part of the clues to how this niche is organized has to do with these basal apical organization. And also this has another important clue that we had predicted before, that is that these cells are related to the early radial glia that are also epithelial cells, and the radial glia in turn, are also derived from another epithelial cell. So it goes from neuroepithelium to radial glia, to a cell that has actually something morphology in the adult, but it's actually retaining epithelial characteristics. So that's in terms of the progenitors. In terms of the C cells, we know very little. But we think that there is, we always see them closely interacting with C cells with the B cells, so they form clusters right next to the C cells, so we believe that there might be some interactions here that are important factors, that D cells are feeding these C cells. This remains a big question, because we do not know how many times these cells divide, how specified they are, how much program there is in the division of these cells, so a lot of this is unknown. And most likely, within these cells is that programs to start building neurons start to be created. And then from these cells generate the A cells, and then we know a little bit more. So this niche integrates, as I said before, birth, amplification, and migration. And one of the interesting questions is that these cells have migrate actually very far, go very very long distances. So how come they don't get lost in the brain? And what we have seen is that the organization of these epithelium, of ependymal cells with their cilia, plus chemo-repellents as Slit one and two actually there are secreting cerebrospinal fluid creating a directional gradient that actually moves these cells forward in the right directions to get to the olfactory bulb. So you can see the niche integrates both signals to regulate the behavior of the cells, signals that are still largely unknown to regulate the amplification of these cells, and this is very much related to cancer, because if these cells stop 2009 Web Conference with Dr.
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