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Using Stem Cells to Prevent Anemia and Other Blood Disorders

May 2015

Stem cells can generate any type of cell in the body, but when they become too active and divide too often, they risk acquiring cell damage and mutations. In the case of blood stem cells (also called hematopoietic stem cells or HSCs), this can lead to blood cancers, a loss of blood cells and an impaired ability to fight disease.

Karsten Sauer is an associate professor at The Scripps Research Institute.

A team of scientists at The Scripps Research Institute (TSRI) has discovered that a particular enzyme in HSCs is key to maintaining healthy periods of inactivity. The discovery could lead to new therapies for diseases such as bone marrow failure syndrome, anemia, leukemia, lymphoma and immunodeficiencies.

The team's findings show that animal models without this enzyme, called Inositol trisphosphate 3-kinase B (ItpkB), experience dangerous HSC activation and ultimately succumb to lethal anemia.

“These HSCs remain active too long and then disappear,” said TSRI Associate Professor Karsten Sauer, senior author of the new study. "As a consequence, the mice lose their red blood cells and die."

HSCs are a type of adult stem cell that live in little niches in the bone marrow. They are normally inactive, or “quiescent,” and only divide to self-renew about every two months.

However, when mature blood cells are lost, for example, through severe bleeding or during infections, HSCs become activated to generate new “progenitor” cells. Progenitor cells replenish the blood supply and produce immune cells to fight disease. Once the blood cells have been replenished, the HSCs become quiescent again.

This means normal HSCs only ramp up production during times of need. Disease strikes when HSCs stop regenerating or become hyperactive. For example, chronic myelogenous leukemia is caused by overproduction of certain white blood cells in the bone marrow.

Dr. Sauer and his colleagues set out to better understand the mechanisms that activate and deactivate HSCs. “Despite the importance of a proper 'work-rest balance' for HSCs, we know amazingly little about the molecular mechanisms controlling this,” said Dr. Sauer.

The team focused on ItpkB because it is produced in HSCs, and the Sauer lab and others had previously shown that it controls a major signaling pathway in other cells implicated in activating HSC.

The researchers started with a strain of mice that lacked the gene to produce ItpkB. They found that without the enzyme, the mice indeed developed hyperactive HSCs that continually multiplied until the HSCs stored in the bone marrow were exhausted. Without these stem cells, the mice could no longer produce red blood cells. As a result, they died due to severe anemia.

“It's like a car – you need to hit the gas pedal to get some activity, but if you hit it too hard, you can crash into a wall,” said Sauer. “ItpkB is that spring that prevents you from pushing the pedal all the way through.”

The researchers then linked the hyperactive HSC to a complex signaling pathway within the stem cell regulated by ItpkB. To halt the abnormalities in the signaling process caused by a lack of ItpkB and prevent the excessive division of HSCs, the team treated animal models with rapamycin, an approved anti-cancer drug.

Sauer says future studies in his lab will focus on studying whether ItpkB has a similar function in human HSCs. “A major question is whether we can translate our findings into innovative therapies,” said Sauer. “If we can show that ItpkB also keeps human HSCs healthy, this could open avenues to target ItpkB to improve HSC function in bone marrow failure syndromes and immunodeficiencies or to increase the success rates of HSC transplantation therapies for leukemias and lymphomas."

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