Boosting Production of Blood-Forming Stem Cells
Research in Zebrafish may help patients needing Bone-Marrow Transplants
Researchers have discovered a way to replenish blood cells more quickly after exposure to radiation. Studies of a mutant strain of zebrafish, colorfully named mind bomb, have identified key genetic regulators that boost production of blood-forming stem cells.
The finding could lead to ways to supercharge production of hematopoietic stem cells (HSCs) in cancer patients who have received bone marrow transplants (also known as stem-cell transplants) to restore their blood-forming system after chemotherapy or radiation. Supercharging could also enhance the effectiveness of such transplants in patients with aplastic and sickle-cell anemias, said the researchers, led by Leonard I. Zon, a Howard Hughes Medical Institute investigator at Children's Hospital Boston. They report their findings in the October 2005 issue of the journal Genes and Development.
"The regulatory program for self-renewal of stem cells is a black box - very little is known about what controls the ability of a stem cell to replicate," said Zon.
Zon and colleagues focused on the possible role of a regulatory gene called Notch in governing HSC production. Notch produces a transcription factor, a protein that controls the activity of a wide range of genes. Experiments by other researchers had hinted that Notch, known to regulate a wide range of cellular processes, might also play a role in HSC replication.
The researchers chose the zebrafish for their studies because it is easily manipulable and has a blood-forming system that shares many similarities with that of mammals. But they had a problem: activating Notch too early in zebrafish development would have broad effects on cell differentiation - unwanted in their experiment, whose aim was production of undifferentiated HSCs.
Zon and his colleagues circumvented that problem by taking an entirely different approach. They began with a zebrafish mutant called mind bomb, which lacks Notch signaling and fails to produce HSCs when it matures into an adult. But by using some clever genetics, the researchers arranged for Notch signaling to be activated only when adult fish were exposed to a brief pulse of heat. By employing this technique on adult fish, they avoided the consequences that would result from activating Notch earlier in development. When the researchers gave the fish a pulse of heat, they found that the fish began to produce more HSCs.
The researchers traced the Notch regulatory pathway further, finding evidence that Notch controls another gene called runx1, which, in turn, regulates HSC production. They then tested whether activating the Notch-Runx pathway could restore HSC production in fish whose stem cell production had been damaged by radiation exposure.
"It was, in essence, a clinical trial on the fish, in which we sub-lethally irradiated them, then added heat to activate Notch," said Zon. "We found that the blood counts recovered far more quickly in the fish. This suggests that if we had a pharmaceutical compound to activate Notch transiently, it could restore the blood system more quickly in patients who are given stem cell transplantation." According to Zon, transient activation of Notch would be desirable, because long-term activation may trigger development of lymphoma.
In a new set of studies, Zon and his colleagues are tracing the Notch regulatory pathway for HSC formation. They are also using genetic and chemical approaches to explore the machinery of HSC production in the aorta of the fish, and plan to search for compounds that can activate those stem cells directly.
Caroline Erter Burns, Elizabeth Mayhall, and Jennifer Shepard, who are members of Zon's laboratory, and David Traver of the University of California, San Diego, were co-authors of the article.