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Hematopoietic stem cells and progenitor cells: their role in normal blood formation 2

Part 2 of 2
Published on March 5, 2014   45 min

A selection of talks on Cell Biology

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0:06
Now I'd like to just take each pathway and discuss what goes on as you mature from the progenitor. And we're showing here the CFU-GM and its ability to give rise under the influence of G-CSF to granulocytes, and under the influence of M-CSF to monocytes.
0:34
Granulopoiesis takes about five to seven days from the progenitor stage to the production of the mature polymorph with its characteristic segmented nucleus.
0:53
This is now to describe one of the cytokines that's become very important because of its clinical use as the granulocyte-colony stimulating factor. It selectively promotes the generation of neutrophils and it induces proliferation and differentiation of the myeloid progenitor cell. It is required at every step throughout the differentiation lineage. It's not just an initiator of differentiation. Differentiation requires it even at the terminal stage of maturation. And if the terminal maturation does not occur, cells can be generated that are partially differentiated, and they have completely different properties. They become myeloid derived suppressor cells, which actually behave as suppressors of the immune system. They inhibit T lymphocytes, and they actually favor the production of tumors. They're the Darth Vaders, if you will, of the hematopoietic system. But if they're allowed to differentiate completely to neutrophils, the neutrophil is a major protector of the body against bacterial infection, and it also has very potent activities in killing tumor cells. It uses the same mechanism to kill bacteria by throwing out a net, comprised of its nuclear DNA, to surround the bacterium or the tumor cell and releasing its granule content of toxic substances and kill quite effectively. When it does so, it dies and has to be replaced by a new population of neutrophils that migrate to the site of inflammation or the tumor site. It has no effect on the more primitive cells outside the G-CSF progenitor pathway. But interestingly, if you give G-CSF for a number of days, it actually mobilizes, from the bone marrow into the peripheral blood, hematopoietic stem cells. The way it does this is it actually crowds the bone marrow out with differentiating granulocyte cells. And this crowding actually results in pushing out the stem cells from their niche. So it's almost a mechanical crowding out process that results in this mobilization, together with some enzymes that cleave certain tethering molecules such as the integrins and some of the bound cytokines. So clinically, G-CSF has a major use in stem cell harvesting, stem cell mobilization to transplantation purposes. But its major use is to prevent the decline, or at least reduce the decline, in neutrophils following chemotherapy or radiation therapy in patients. It is the decline and the loss of neutrophils that make patients very susceptible to infection. And there was a lot of morbidity and mortality associated with high-dose chemotherapy until G-CSF came along and could be used to greatly reduce the period of neutropenia when a patient was very susceptible to these infectious events.

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