Fertilizer for stem cells
Blood stem cells will be produced on an industrial scale
NanoNewsNet based on materials from Weill Cornell Medical College:
New Method Developed to Expand Blood Stem Cells for Bone Marrow TransplantA research team led by scientists at Cornell University's Weill College of Medicine may have solved the main problem associated with obtaining large quantities of adult hematopoietic stem cells needed for bone marrow transplantation in the laboratory.
Scientists from Weill Cornell and their colleagues from Memorial Sloan Kettering Cancer Center have designed a protein that allows increasing the population of hematopoietic stem cells (HSCs) after their extraction from the donor's bone marrow. This engineered protein preserves the proliferating HSCs in a stem state, which means that they will not differentiate into specialized types of blood cells before transplantation to the recipient.
Finding a compatible bone marrow donor is a difficult task, and bone marrow sampling itself – its extraction with a needle from a large bone under general anesthesia – is a difficult and painful process for a donor. The number of bone marrow cells obtained as a result of one sampling is often not enough to carry out a successful transplant, and in many cases the donor has to undergo several such procedures.
The ability to receive a large number of healthy HSCs outside the body means that fewer stem cells can be taken from donors. In addition, adult blood stem cells can be frozen and stored in a jar for subsequent reproduction and clinical use.
"Our immediate goal is to find out whether it is possible to take a smaller number of stem cells from a donor and multiply them for transplantation. In this case, there will probably be more people willing to become donors," says study leader Dr. Pengbo Zhou, professor of pathology and laboratory medicine at Weill Cornell. "If there are a lot of donors, we will be able to type cells before they are frozen and placed in a bank and we will know all their immune characteristics. When a patient needs a bone marrow transplant to treat cancer or another disease, we will be able to find compatible cells, multiply them and use them for transplantation."
In the future, such an option will become available – to put your own bone marrow in the bank for possible use in the future, Dr. Zhou believes.
"A person's own blood stem cells are not only the best treatment for many types of blood cancer – they can be useful for other purposes, for example, to slow down aging."
Problems with the extraction of donor bone marrow have already led to several attempts to reproduce hematopoietic stem cells in the laboratory. The authors of these studies focused on the transcription factor HOXB4, which stimulates the proliferation of HSCs. The more HOXB4 protein there is in stem cells, the more they self-renew and increase their population.
The new method allows obtaining large amounts of healthy blood stem cells outside the body,
making it possible to produce them on an industrial scale. (Photo: Weill Cornell Medical College)
As it turned out, the HOXB4 protein can be directly implanted into extracted bone marrow stem cells. All that needs to be done is to add to this protein a small section that, acting as a vehicle, conducts HOXB4 through the cell membrane directly into its nucleus. But the half–life of natural HOXB4 is very short - about one hour. This means that for the reproduction of blood stem cells, HOXB4 must be constantly added. Since proteins are not cheap, this process is expensive and impractical.
Dr. Zhou and his group found out why the HOXB4 protein lives so short in HSCs if cells lose their protective niche. It turned out that it becomes a target for destruction, so that stem cells can begin differentiation, that is, transform into different types of adult blood cells.
The researchers found that one of the proteins, CUL4, performs the task of recognizing HOXB4 and makes it visible to the cellular mechanisms of protein degradation. CUL4 recognizes HOXB4 due to the four amino acids found on its surface.
Researchers have developed a synthetic HOXB4 protein in which the destruction signal is masked. This allowed him to increase his half-life to 10 hours. The engineered HOXB4 copes well with its task of multiplying stem cells while preserving all their stem properties. As a result, cells with engineered HOXB4 demonstrate a higher ability to reproduce than those that have received a natural version of this protein. Animal experiments have shown that transplanted engineered human stem cells retain their properties in the bone marrow of mice.
In order to obtain the amount of HSC needed for transplantation to a patient or for placement in a bank, the HOXB4 engineering protein can be injected approximately every 10 hours.
"Our work shows that we can overcome one of the main technical obstacles in the reproduction of adult blood stem cells, making it possible to obtain them on an industrial scale for the first time," concludes Dr. Zhou.
Article by Lee et al. Improved ex vivo expansion of adult hematopoietic stem cells by overcoming CUL4-mediated degradation of HOXB4 published in the journal Blood
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