Researchers at the Duke Comprehensive Cancer Center have identified a critical switch that turns on a blood stem cell's prized ability to regenerate itself while also producing a variety of daughter cells. These daughter cells are capable of becoming mature blood and immune system cells.

The switch is a protein called Notch that resides on the surface of stem cells. When Notch activity is turned off, stem cells quickly lose their potency and begin to change into more mature cells that can no longer produce new blood-forming cells.

Previous research had suggested that activation of Notch -- a protein known to be crucial to the development of embryos in virtually all animals from flies to humans -- could also influence growth of blood-forming cells. But whether or not it was required for proper development of blood forming stem cells and its exact role in this context was unknown, said Tannishtha Reya.

Reya and colleagues have studied mice developed by Nicholas Gaiano, from Johns Hopkins University. These mice contain an engineered gene sequence capable of producing a fluorescent signal when Notch signaling is activated.

The fluorescent protein allowed them to track where Notch was active during blood cell development and to see when it had been turned off. The studies revealed strong signals in the portion of bone marrow where the potent hematopoietic stem cells reside. The levels of Notch signal decreased rapidly as these stem cells committed to becoming fully mature cells.

Moreover, when the researchers selectively inactivated the Notch gene, the stem cells could not maintain themselves and quickly began to change into more mature cells.

" When we inhibited Notch activity in stem cells, they rapidly committed and differentiated into mature lineages," said Reya. " That finding, together with the data showing Notch function is shut off physiologically as cells commit to specific lineages, suggests that turning off Notch is a mechanism that allows stem cells to become sensitive to differentiation cues. Thus, Notch appears to act as a switch that can influence the balance between self-renewal and commitment."

The results also helped clarify the role of another stem cell signal called Wnt, which Reya and her colleagues showed in previous studies is also necessary for normal stem cell survival and proliferation. Reya said the two signals – Notch and Wnt -- likely have distinct roles in self-renewal or regeneration.

" Our current work suggests that, at least in hematopoietic stem cells, Notch may have a dominant role in maintaining stem cells in an undifferentiated state while Wnt may have a dominant role in proliferation and survival. "

Understanding the signals that both maintain stem cells in their undifferentiated state and allow them to proliferate could enable a patient's or donor's hematopoietic stem cells to be grown in the laboratory, providing an enriched source of stem cells for transplantation.
The findings may also help explain why aberrant Notch signaling leads to T cell leukemias and other cancers.

In blood cancers such as leukemias and lymphomas, the blood cells fail to mature and they multiply abnormally.
Physicians have successfully treated acute promyelocytic leukemia ( APL ) using a drug called Retinoic Acid, which forces the cancerous cells to mature or differentiate. Forcing the cells to mature also stops excessive proliferation and restores the natural cycles of cell death, effectively stopping the cancerous process.

" If Notch promotes leukemia by locking cells in an undifferentiated state, then inhibiting Notch would force leukemic cells to differentiate and could potentially be used as a therapy." Reya said.
The findings have been published in Nature Immunology.

Source: Duke University Medical Center, 2005


XagenaMedicine2005