Protein governs stem cell self-renewal, may lead to better treatments for blood diseases

Activating a protein causes blood stem cells to self-renew at least twelvefold in laboratory conditions, according to a new study by scientists from the University of California Los Angeles and published published in the journal Nature.

Blood stem cells, also known as hematopoietic stem cells, are found in the bone marrow, where they self-renew as well as differentiate to create all types of blood cells. Bone marrow transplants have been used for decades to treat people with some diseases of the blood or immune system. However, bone marrow transplants have significant limitations. Finding a compatible bone marrow donor is not always possible, the patient's immune system may reject the foreign cells, and the number of transplanted stem cells may not be enough to successfully treat the disease, the researchers said.

When blood stem cells are removed from the bone marrow and placed in laboratory dishes, they quickly lose their ability to self-renew, and they either die or differentiate into other blood cell types. The research goal of making blood stem cells self-renew in controlled laboratory conditions, would open a host of new possibilities for treating many blood disorders, among them safer genetic engineering of patients' own blood stem cells. It could also enable scientists to produce blood stem cells from pluripotent stem cells, which have the potential to create any cell type in the body.

To uncover what makes blood stem cells self-renew in a lab, the researchers, led by Hanna Mikkola, MD, PhD, and Vincenzo Calvanese, PhD, analyzed the genes that turn off as human blood stem cells lose their ability to self-renew, noting which genes turned off when blood stem cells differentiate into specific blood cells such as white or red cells. They then put the blood stem cells into laboratory dishes and observed which genes shut down. Using pluripotent stem cells, they made blood stem cell-like cells that lacked the ability to self-renew and monitored which genes were not activated.

The researchers found that the expression of a gene called MLLT3 was closely correlated with blood stem cells' potential to self-renew and that the protein generated by the MLLT3 gene provides blood stem cells with the instructions necessary to maintain its ability to self-renew. It does this by working with other regulatory proteins to keep important parts of the blood stem cell's machinery operational as the cells divide.

From there, the researchers wondered if maintaining the level of the MLLT3 protein in blood stem cells in lab dishes would be sufficient to improve their self-renewing abilities. Using a viral vector, a specially modified virus that can carry genetic information to a cell's nucleus without causing a disease, the team inserted an active MLLT3 gene into blood stem cells and observed that functional blood stem cells were able to multiply in number at least twelvefold in lab dishes. Further, MLLT3 made the blood stem cells self-renew at a safe rate; they didn't acquire any dangerous characteristics such as multiplying too much or mutating.

The next steps for the researchers include determining what proteins and elements within blood stem cell DNA influence the on-off switch for MLLT3, and how this could be controlled using ingredients in the lab dishes. With that information, they could potentially find ways to switch MLLT3 on and off without the use of a viral vector, which would be safer for use in a clinical setting. Multiplying blood stem cells in conditions outside the human body could greatly improve treatment options for blood cancers like leukemia and for many inherited blood diseases, the researchers said.