Scientists Find Missing Ingredient For Blood Renewal

The inability to get human blood stem cells, or hematopoietic stem cells (HSCs), to self-renew in the laboratory is holding back progress in treating leukemia and other blood diseases.
Now, a new study from the University of California, Los Angeles (UCLA) suggests that the answer may lie in a particular protein — the activation of which can greatly expand HSCs in
The UCLA team found that a protein called MLLT3 is a key regulator of HSC function. The protein is present at high levels in the HSCs of human fetuses, newborns, and adults. However,
cultured HSCs have low levels of MLLT3.
In a recent Nature paper, the researchers report how manipulating the gene responsible for making the protein led to a more than the 12-fold expansion of transplantable" HSCs.
The senior author of the study paper is Hanna K. A. Mikkola, a professor of molecular, cell, and developmental biology at UCLA. She has been studying HSCs for more than 20 years.
Although we’ve learned a lot about the biology of these cells over the years, says Mikkola, one key challenge has remained: making [HSCs] self-renew in the lab.
We have to overcome this obstacle to move the field forward, she adds.
All tissues and cells of the body rely on blood cells for nourishment and protection. To fulfill such a relentless and onerous task, blood cells must be able to replenish themselves. In adults,
blood cells and skin cells have the greatest replenishment capacity of any tissue.
The job of making new blood cells falls to HSCs. Every day, the human body makes billions of new blood cells, thanks to HSCs, which also make immune cells.
HSCs reside in bone marrow, where they self-renew and mature into different types of blood and immune cells. People with certain diseases of the blood or immune system — such as leukemia — need fresh supplies of HSCs to make new cells. For decades, doctors have used bone marrow transplants to boost their supplies.
However, there are limits on the extent to which bone marrow transplants can offer a solution. For instance, it is not always possible to find a matching donor, or the recipient's body might
reject the transplanted cells.
Another problem that can arise is that the number of transplanted HSCs may not be enough to generate sufficient blood or immune cells to treat the disease. Scientists have tried to culture HSCs in the laboratory as an alternative to bone marrow transplants. However, various attempts to transplant cultured HSCs have hit a common problem:

HSCs that scientists have removed from bone marrow soon lose their capacity for self-renewal in culture. Once HSCs lose the ability to make new copies of themselves, the only future that they have is either to differentiate into specialized cells or to die. For the new study, Prof. Mikkola and her team looked at what happened to genes as the HSCs
lost their ability to self-renew in the laboratory. They saw that some genes switched off when this happened. The genes that switched off varied according to the types of cells that the HSCs formed.
To take a closer look, the team generated HSC-like cells from adult pluripotent stem cells that could not self-replicate and then observed their gene activity. This experiment showed that there was a strong link between the self-renewal ability of HSCs and the activity of the MLLT3 gene. It seems that high expression of MLLT3 ensures a plentiful supply of its protein, which bears the
instructions necessary for HSCs to self-renew. The protein helps the HSC’s machinery keep working while the cell makes a copy of itself.
Further experiments revealed that inserting an active MLLT3 gene into the nucleus of HSCs in laboratory culture increased their ability to self-replicate by a factor of 12.
If we think about the amount of blood stem cells needed to treat a patient, that’s a significant number.  Other studies that have tried to get HSCs to self-renew in culture have used small molecules.
However, Prof. Mikkola and her team experienced problems with that approach. They found that the cells were not able to maintain the levels of MLLT3 protein, and they did not work well when the team transplanted them into mice.
The team found that combining the small molecule method with MLLT3 gene activation generated HSCs that integrated properly into bone marrow in mice.
Those HSCs also produced all the correct types of blood cells and retained their ability to self- renew. A concern that scientists have about producing transplantable HSCs in the laboratory is ensuring that they operate correctly once they are in the body. The HSCs have to be able to self-replicate at the right place, and they must not acquire mutations
that could lead to diseases such as leukemia. It appears that ensuring stable levels of MLLT3 protein meets these requirements. The researchers are now working on methods of manipulating MLLT3 more safely and easily.


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