Friday, 22 March 2013

New technique allows researchers to grow hematopoietic stem cells "on an industrial scale"

A team of researchers from the Weill Medical College of Cornell University and the Memorial-Sloan Kettering Cancer Center has developed a new method to greatly expand, in the laboratory, the numbers of hematopoietic stem cells (HSCs) after they have been extracted from bone marrow tissue. The researchers say that their method is of great importance as it allows, like no other previously described, the mass production of MSCs for clinical use.

When a patient is in need of a bone marrow transplant there are two main problems he has to face. The first one is it to find a suitable donor-match and the second is to extract enough amounts of HSCs for the transplant. Unfortunately, in many cases a single harvest is not enough and additional ones are often required.

Being able to expand the number of HSCs in the laboratory would allow doctors to deal easily with the latter problem, even allowing them to cryo-preserve some cells for future use. However, such a method doesn't exist yet.

Pengbo Zhou, senior author of the study, says that their newly-developed technique may help overcome this problem as it makes it possible, for the first time, to grow in the lab HSCs "on an industrial scale".

Zhou explains that the Homeobox protein Hox-B4 (HOXB4) has been previously found to stimulate HSCs into replicating, thus increasing their number. "The more HOXB4 protein there is in stem cells, the more they will self-renew and expand their population" he says. However, previous attempts to transfer the gene responsible for producing this protein have failed as HSCs are quite resistant to gene transfer. For instance, in the past researchers have tried to insert HOXB4 proteins into extracted HSCs. "All you do is add a little tag to the protein, which acts like a vehicle, driving the proteins through the cell membrane, directly into the nucleus", adding that when introduced via this method the protein has a very small half-life, of only about an hour. As a result, it is essential to introduce new HOXB4 proteins in a constant basis for the cells to continue replicating. As the proteins have a very high cost, this makes the process both "expensive and impractical".

In this study, the researchers investigated why HOXB4 doesn't last long in HSCs, following their extraction from bone marrow tissue. They discovered that the HOXB4 protein inhibits the differentiation process and is targeted for degradation. "HOXB4 prevents blood stem cells from differentiating, while, at the same time, allows them to renew themselves" said Dr. Zhou. They also found that another protein, called CUL4 is responsible for recognising and marking HOXB4 for destruction. This occurs because HOXB4 carries a sequence of 4 amino-acids that act as a "destruction signal".

The researchers then created an artificial HOXB4 protein with a "scrambled" aminoacidic sequence. Next, they used bacterias to produce large amounts of the new engineered protein and introduced the proteins into lab-isolated HSCs. Zhou says that the scrambled destruction signal increased HOXB4's half-life from a a mere 1 hour to 10, without interfering with the capacity of HSCs to differentiate into other cells.

"As a result, cells receiving the engineered HOXB4 demonstrated superior expansion capacity than those given natural HOXB4 protein. Animal studies demonstrated that the transplanted engineered human stem cells can retain their stem cell-like qualities in mouse bone marrow." said Zhou.

The researchers now aim to start taking HSCs donations to see if they can put their findings to use. Hopefully, they will be able to create large amounts of HSCs by taking donations containing less cells than the standard ones do. 

 "If many people donate, then we can type the cells before we freeze and bank them, so that we will know all the immune characteristics. The hope is that when a patient needs a bone marrow transplant to treat cancer or another disease, we can find the cells that match, expand them and use them."

Zhou even envisions a future in which patients are able to store their own HSCs for future use, as autologous HSCs are often the best treatment for various diseases, including many different types of leukaemia.


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References
Lee, J., Shieh, J., Zhang, J., Liu, L., Zhang, Y., Eom, J., Morrone, G., Moore, M., & Zhou, P. (2013). Improved ex vivo expansion of adult hematopoietic stem cells by overcoming CUL4-mediated degradation of HOXB4 Blood DOI: 10.1182/blood-2012-09-455204

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