CD133: A new way for cells to share molecules

One of the masters of regeneration in the human body is the liver. It’s so good at it, that if you cut out 80% of someone’s liver, they’ll grow a new one from what’s left. In fact surgeons take advantage of this quite often when carrying so-called “living” liver transplants. We know why it does this: it’s frequently injured by all the toxins we ingest, including alcohol. But how does it do it? About 10 years ago, team at UCSD thought they had the answer in a gene that, knocked out, seemed to disable liver regeneration, at least in the dish. But when they looked in vivo, Gen-Sheng Feng and his colleagues were surprised to see that regeneration was still taking place, albeit slowly, and the regenerating cells all formed in clusters. They’ve now looked a bit more closely, and made a potentially staggering discovery: a protein called CD133 appears to be forming small bubble-like vesicles inside - and crucially between - the regenerating cells. He thinks this might be a new way that cells can share limited resources. In this instance, some compensatory growth signal is spreading through the clusters. But the bigger picture is that this same molecule is also active in cancer cells. So, as he explains to Chris Smith, is this also how tumour populations operate, and even become drug resistant?

Gen-Sheng - Some of these cells can still proliferate without that gene. So means what? By knocking out that gene, we found the liver regeneration was impaired, delayed but not completely blocked. It can still finish or complete the liver regeneration, although the time lapse was longer. So we want to understand why these cells can do without the important gene.

Chris - Do you think that's because there's something making up for the absence of that gene in some cells or do you think something else is going on?

Gen-Sheng - Yeah, that's so called compensatory mechanism, right. So in dissecting that mechanism, we found that in the gene knockout liver, these dividing liver cells will all form clusters in the liver, When we dissect the liver section to look at specifically. So at the beginning we thought these cells must be derived from, so-called progenitor cells or stem cell. But then with that hypothesis, we searched for a lot of biomarkers for stem cell or progenitor cells. Indeed. But we only found CD133 in these dividing cells. These dividing cells are actually negative for all the other progenitor cell markers that we screened and eventually we found that these are mature liver cells. They are not progenitor cells, not stem cells. So that led us to dig into a new field and eventually we found that actually CD133 labels a vesicle that these cells produce in response to the deficiency of cell division.

Chris - So let's unpack that a bit then. You knocked out what you thought was the linchpin behind regeneration and were quite surprised then to see that some liver cells limp along and managed to regenerate anyway and they're all in bunches in clusters. So you thought, aha, there must be some kind of stem cell that's doing that, but you couldn't find any evidence it was a stem cell. They all looked like grownup mature cells, except they did have this magic marker CD133 MM-Hmm <affirmative>. And you are saying this unlocks some special new field. What's the CD133 doing then?

Gen-Sheng - CD133 is a cell surface protein. It has five transmembrane domains. But how CD133 functions in stem cell or non stem cells is not clear no matter how and nobody knows what's the function of CD133, how it regulates, even if it's important. Right. And we found actually CD133 labelled vesicles in many cases inside the cell. More importantly, we found at the low resolution microscope CD133 labelled bridges between these dividing cells. So that's led us to hypothesise that CD133 may mediate a new mechanism of cell cell communication.

Chris - Goodness. So you are saying this molecule, which is sometimes on cell surfaces, in your hands in these experiments ended up around little packets inside the cells and occasionally you could see threads connecting the cells. Mm-Hmm. <Affirmative>. Mm-Hmm. <Affirmative>. So there's like a portal being opened up between adjacent cells. Is that a physical connection? Can things go between cells down those connections then?

Gen-Sheng - Yes. That's a great question. We presented some data but not sufficient. We need to do further experiment to demonstrate that this vesicle is indeed migrating between cells, so letting cells share materials, for example messenger RNAs and the proteins that are required for cell proliferation. That's what we are still working on.

Chris - So your hypothesis then is the reason that some of these cells regenerate is because mm-Hmm, <affirmative>, they've got enough, even though there's a knockout of the particular linchpin gene, there is some compensatory growth mechanism which is being shared by these cells and it's enabling them to grow nonetheless. And that's why you see these clusters of cells connected together in this way using this new mechanism you've identified, possibly mediated by this CD133 conduit as it were to share resources between the cells?

Gen-Sheng - Yes, actually we do have evidence that demonstrate these deficient cell missing different material like this cell missing A, another cell missing B. So if they mutually share, then they are not missing A or B, they have all the material that are essential. So that's why I think we discovered a new function of CD133, and why this is so important.

Chris - CD133 has had the finger pointed at it in a number of different settings, particularly as a cancer stem cell marker or a progenitor marker. Do you think then, this is partly how cancer cells work as well. Are they sharing growth resources or compensating for some genetic lesions that mean that the cancers grow robustly and even develop resistance against chemotherapy by using things like CD133 in order to reinforce the cancer as a population of cells?

Gen-Sheng - Indeed, that's a real question and the issue that make us excited about this discovery, because cancer stem cell are a new concept in the cancer research field, but there are disagreements about this concept or data. There are indeed controversial data about the existence of cancer stem cell. However, there is a very good evidence to correlate the CD133 expression and the tumour recurrence. So with our data now we can explain all the controversy, I believe, because once you have the compensatory mechanism mediated by CD133 positive vesicles turned on, they will become resistant to the drugs and that will lead to tumour recurrence. So this kind of recurrence does not need new mutation in cancer cells. So that's why I think this will be a very quick mechanism to develop drug resistance and therefore cancer recurrence.