Cells reproduce in captivity
Researchers from the University of California at Los Angeles have discovered a protein that affects the ability of human blood stem cells to self-renew. In a study published in the journal Nature, the group reports that activation of this protein in the laboratory caused blood stem cells to self-renew.
The division of blood stem cells outside the human body will help significantly improve the treatment of oncological diseases of the blood – leukemia, as well as many hereditary blood diseases.
Dr. Hanna Mikkola, the head of the study, has been studying blood stem cells for more than 20 years. Over the years, she managed to learn a lot about cell biology, but one important problem remained unresolved: to make stem cells self-renew in a laboratory. Overcoming this obstacle can move science forward.
Blood stem cells (hematopoietic stem cells, hemocytoblasts) they are contained in the red bone marrow, where they self-renew and differentiate, creating all types of blood cells.
Bone marrow transplantation has been performed for decades to treat people with certain diseases of the blood or immune system. However, this operation has significant limitations: the search for a compatible bone marrow donor does not always bring results, the patient's immune system may reject foreign cells, and the number of transplanted stem cells may not be sufficient for successful treatment of the disease.
When blood stem cells are extracted from the bone marrow and placed in a culture medium, they quickly lose the ability to self-renew and either die or differentiate into mature blood cells. Creating conditions for self-renewal of blood stem cells in controlled laboratory conditions would open up many new opportunities for the treatment of a number of blood diseases, including safer genetic engineering of patients' own blood stem cells. It will also make possible the production of blood stem cells from induced pluripotent stem cells.
The researchers analyzed genes that turn off when human blood stem cells lose their ability to self-renew, and genes that turn off when blood stem cells differentiate into mature blood cells. They then placed the blood stem cells in a nutrient solution and observed which genes were switched off. From pluripotent stem cells, they obtained cells that, like blood stem cells, lacked the ability to self-renew, and observed which genes were not activated.
They found that the expression of the MLLT3 gene is closely related to the potential of blood stem cells for self-renewal and that the protein encoded by it provides blood stem cells with the instructions necessary to maintain the ability to self-renew. The MLLT3 protein contacts regulatory proteins so that important steps of the blood stem cell renewal mechanism work when cells divide.
The researchers tested whether maintaining the level of MLLT3 protein in blood stem cells in vitro would be sufficient to improve their ability to self-renew. Using a viral vector – a modified virus that can carry genetic information into the cell nucleus without causing disease – the team inserted the active MLLT3 gene into blood stem cells and found that functional blood stem cells can multiply in vitro, increasing the number of cells by at least twelve times.
For the treatment of one patient, this is a sufficient number of cells. But it is also important that these cells continue to function after transplantation.
Recent studies have identified small molecules that help human blood stem cells divide in the laboratory. Mikkola's group used them, and it was noticed that the self-renewal of blood stem cells generally improved, but the cells could not maintain the proper level of MLLT3, and they did not function after transplantation to mice.
The combined method, which combines the effect on blood stem cells of the detected molecules and the delivery of the active MLLT3 gene, creates blood stem cells that integrate well into the bone marrow of mice and effectively produce all types of blood cells.
It is important to note that MLLT3 causes blood stem cells to self-renew at a safe rate, that is, they did not acquire any dangerous characteristics and mutations that could lead to leukemia.
Further work will be devoted to the determination of proteins and DNA fragments of blood stem cells that affect the MLLT3 gene, as well as the search for ways to control this process in the laboratory. With this information, researchers can find ways to turn MLLT3 on and off without using a viral vector – this would be safer for use in a clinical setting.
Article V.Calvanese et al. MLLT3 governs human haematopoietic stem-cell self-renewal and engraftment published in the journal Nature.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on UCLA materials: Researchers identify protein that governs human blood stem cell self-renewal.