Researchers See Twelvefold Increase in Blood Stem Cell Renewal in Lab Dishes with Recently Discovered Protein

Researchers See Twelvefold Increase in Blood Stem Cell Renewal in Lab Dishes with Recently Discovered Protein

Researchers at the University of California Los Angeles (UCLA) have discovered a protein that causes blood stem cells to renew at twelve times the rate in vitro. The discovery could lead to more effective treatments for a range of inherited blood diseases and blood cancers such as leukemia.

Blood stem cells reside in the bone marrow where they self-renew and can differentiate into all types of blood cells. Patients with diseases of the blood are treated with bone marrow transplants, although finding a suitable donor is a challenge, as is ensuring enough stem cells are transplanted to cure the disease.

To ensure enough stem cells are available, blood stem cells could be harvested and multiplied under laboratory conditions; however, blood stem cells tend to lose their ability to self-renew in the lab. The cells either differentiate into the wrong type of blood cell or they die.

The UCLA researchers conducted a study to determine what factors were responsible for making blood stem cells self-renew in laboratory conditions. They analyzed the genes that switched off when blood stem cells lost their ability to self-renew in laboratory dishes.

One gene – MLLT3 – was found to play a role in maintaining the stem cells’ ability to self-renew. The protein that the active gene encoded maintained the self-renewing ability of blood stem cells by interacting with several regulatory proteins. With the gene active, and the protein being synthesized, the stem cells kept their self-renewing capabilities when they divided.

The researchers used a viral vector to insert an active MLLT3 gene into blood stem cells in lab dishes and observed a 12-fold increase in multiplication of the cells in lab dishes. However, increasing the number of stem cells in the lab is only part of the problem, as the stem cells must be able to differentiate into healthy cells. What is needed is quantity and quality to ensure that when the stem cells are transplanted into patients, they can produce healthy blood cells.

Using small molecules to encourage the cells to multiply in the lab, self-renewal improved; however, the stem cells were not able to maintain sufficient levels of MLLT3 to allow them to function when transplanted into mice. The researchers’ technique, of using small molecules and also inserting the active MLLT3 gene, ensured that the blood stem cells integrated when implanted in mice, retained their self-renewing abilities, and were able to differentiate into all blood cells. When introduced, the blood stem cells self-renewed at the desired rate and did not mutate to produce abnormal blood cells.

The researchers are now investigating what factors are responsible for switching off the MLLT3 gene to determine how the gene could be switched on under laboratory conditions without having to use an engineered virus to deliver the gene into cells.

The researchers’ findings are detailed in the paper – MLLT3 governs human haematopoietic stem-cell self-renewal and engraftment – which was published in Nature on November 27. DOI: 10.1038/s41586-019-1790-2

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