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Thread: Lgr5 - a proper stem cell marker?

  1. #1 Lgr5 - a proper stem cell marker? 
    Forum Cosmic Wizard spuriousmonkey's Avatar
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    In a recent article in Nature the gene Lgr5 was identified as a marker for stem cells in the gut.

    This may not seem as very important to some, but for those who are in the business of stem cells finding a reliable stem cell marker is in fact the holy grail.

    And recently more and more reports have been turning up that our old ideas are bogus.

    The paper in nature used a variety of complex techniques, labeling the cells, the descendants of the cells and characterized the Lgr5 expressing cells. I will not go deep into to this because it's a bit technical.

    I will just go through the most interesting general findings.


    Firstly, the Lgr5 positive cells are actively cycling!!!!

    Compare this to the dogma that stem cells are slowly cycling cells, only dividing once every few weeks or longer. In fact an old method of showing stem cells was to give them a pulse chase of BrdU. BrdU is incorporated into cells that divide and you can show these cells with an antibody. Cells that are not dividing when giving the BrdU pulse do not incorporate it into their DNA.

    So when you give a dose of BrdU at only one timepoint you will label the cells that are dividing at that particular time. When a cell with BrdU divides again, the BrdU is divided between the daughter cell and the original cell and sort of diluted. You can imagine that a normal cell keeps dividing and the BrdU keeps getting diluted till you cannot detect it any more.

    But if a cell is slowly dividing (divides only once every few weeks) and it happens to divide when you give the dose of BrdU you can come back to the tissue after a few weeks, and all the cells that show BrdU labeling have only divided once, or maybe twice.

    But then I saw a recent paper also not too long ago which tested this hypothesis and came to the conclusion that it is not valid for blood stem cells (if I remember correctly).

    And now we see something similar in this paper! Stem cells are NOT slowly dividing in the gut.


    Second import conclusion

    It shows that some of the other proposed stem cell markers are actually not stem cell markers. A common problem in stem cell biology. All the old work has to be re-evaluated based on the new findings, and with the third conclusion in mind, maybe also for the stem cell markers in different organs.


    Third import conclusion
    This stem cell marker, Lgr5, could well be a general stem cell marker. Unpublished results show that it is also present in the stem cells of the hair follicle; the structure that regenerates new hairs.

    Also stomach, and mammary glands seem to have stem cells expressing the same factor.

    It therefore could well be a general marker and therefore the holy grail.


    Reference:
    Nature 449, 1003-1007 (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5


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  3. #2  
    Forum Cosmic Wizard spuriousmonkey's Avatar
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    Maybe I have to give some kind of basic introduction, because I feel I jumped into the deep end and not all of us can swim.

    What is a stem cell niche?

    Scientists disagree a bit on the definition so I just give my own opinion here which is probably a reflection of a consensus.

    The stem cell is a unique cell. It can divide forever and give rise to different kind of cells. The stem cell itself therefore has no final identity as such and we call it undifferentiated. It divides and gives rise to two daughter cells. One remains a stem cell. The other one will differentiate into a specific identity.

    Usually this differentiating cell will first proliferate to generate more cells. Then it starts getting characteristics of a specific cell type, for instance muscle cells, or neurons. When it has acquired all characteristics it is said to have undergone terminal differentiation.

    Is the stem cell a cancer cell? After all cancer cells also divide forever and give rise to differentiated cells?

    No.

    And this is where the stem cell niche comes into play.

    The stem cell niche is the total of stem cells and their environment that controls their function.

    You have a small population of stem cells surrounded by other cells and tissues. All highly organized although often we don't know the specifics. The surrounding cells maintain, stimulate, or inhibit the stem cells by means of regulatory signals. They also regulate the differentiation of the progeny of the stem cells. This is still part of the stem cell niche. So surrounding cells, cell layers or tissues will stimulate the proliferation of the offspring of the stem cells and put them on the right differentiation path by means of cell to cell signaling.

    In cancer there is no formal regulation of the stem cells. The stem cells have broken loose and are on a rampage.

    Of course that doesn't mean that tumors cannot be highly organized. Living tissue always tends to organize itself. It's just that it happens to organize itself in a manner that is useless to the organism in question, and moreover, often detrimental. Bloodvessels are attracted to the tumor. The tumor grows. More bloodvessels, nutrients and tissue are assimilated, etc. A runaway train.

    The stem cell niche is tightly regulated. And we are discovering more and more about this kind of regulation.


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    Forum Cosmic Wizard paralith's Avatar
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    Thanks for sharing this with us, spurious. It's really interesting. So do stem cells have little nodes in the body where they gather, or are they more evenly distributed throughout tissues/organs?
    Man can will nothing unless he has first understood that he must count on no one but himself; that he is alone, abandoned on earth in the midst of his infinite responsibilities, without help, with no other aim than the one he sets himself, with no other destiny than the one he forges for himself on this earth.
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  5. #4  
    Forum Cosmic Wizard spuriousmonkey's Avatar
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    Quote Originally Posted by paralith
    Thanks for sharing this with us, spurious. It's really interesting. So do stem cells have little nodes in the body where they gather, or are they more evenly distributed throughout tissues/organs?
    That is an excellent question. And I wish I had a definite answer. Nobody is really sure. Or should I say that there is dissent among the ranks. '

    Interestingly, the article on which the opening post is based mentioned briefly that in adult mice they found these Lgr5 positive cells throughout the body in different organs in a scattered fashion. And these cells were rare!

    Now they only tested if they were stem cells in the small intestine.

    Which leaves speculation if the other positive cells in the other organs are also stem cells.

    They found for instance cells in the eye, brain, hair follicle, mammary gland, reproductive organs, stomach and intestinal tract.

    You can rest assured that all stem cell researchers who read this article and heard their favourite organ mentioned are now writing to the group who published this paper!

    That doesn't mean that these cells cannot be concentrated in a small region. In the crypt of the gut, the stem cell niche of the gut, the lgr5 positive cells are all located at the bottom of the crypt. But they are not next to each other. And they are not that plentiful. So what is a lump of cells? They are here somewhat lumped, yet separated.

    In other organs we can possibly say that they are more lumped.

    But are they everywhere?

    maybe.
    "Kill them all and let God sort them out."

    - Arnaud Amalric

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