As researchers attempt to take advantage of the potential of adult stem cells in regenerative medicine, understanding the mechanisms that delimit lifespan and longevity of stem cells will be critically important. Researchers have now identified a family of proteins that contributes to the survival and regenerative potential of blood-forming stem cells.
According to the researchers, their findings in hematopoietic stem cells might be relevant to stem cells in other tissues, and provide insights into potential strategies to enhance the longevity of stem cells.
The new knowledge, gleaned from animal studies, could help enhance the viability of blood stem cells used for bone marrow transplants for patients with leukemia.
The lead author of the study, which was published in the January 25, 2007, issue of the journal Cell, was Zuzana Tothova, an M.D./Ph.D. student in the laboratory of Howard Hughes Medical Institute investigator Gary Gilliland. Tothova and senior author Gilliland are at Brigham and Women's Hospital, the Harvard Stem Cell Institute, and Harvard Medical School.
FoxO genes produce proteins called transcription factors that regulate the activity of other genes. Previous research had shown that the FoxO proteins regulate cell survival and proliferation in many tissues, acting in response to signals from growth factors outside the cell, said Tothova.
Studies had shown that aberrant genes that cause some leukemias and lymphomas inhibit FoxO genes, enabling blood stem cells to escape their regulation and proliferate uncontrollably.
“The puzzling finding until now, however, has been that knocking out single members of the FoxO family didn't seem to have much effect on the hematopoietic system,” said Tothova.
“That led us to the hypothesis that they must be functionally redundant in the hematopoietic system,” she said. Thus, Tothova and her colleagues in the lab of Ronald A. DePinho at the Dana-Farber Cancer Institute decided to generate a transgenic mouse in which they could switch off all three relevant FoxO genes—FoxO1, FoxO3 and FoxO4—in the hematopoietic system of adult animals.
Tothova found that the stem cells in the mice lacking all three FoxO proteins contained more reactive oxygen species (ROS) than normal cells. These are highly reactive chemicals that contribute to normal signaling within the cell, but increased levels can be toxic or even lethal to cells.
In a key experiment, Tothova found she could restore the stem cell number and function to normal by introducing an antioxidant chemical that reduced ROS levels.
“The finding that ROS appeared to be the critical determinant of stem cell life span was quite surprising,” said Tothova. “Showing that we could rescue the cells with an antioxidant suggests that the increased levels of these reactive oxygen chemicals were responsible for the changes in the cells that we observed.”
In contrast, Tothova and her colleagues found ROS levels to be unaffected by FoxO loss and normally much higher in myeloid progenitor cells, which use the reactive molecules as weapons to destroy invading microbes.
“These findings give us a better understanding of the molecular mechanisms that limit the lifespan of hematopoietic stem cells,” Tothova said. “This understanding could be beneficial in our ability to extend the lifespan or modulate longevity of stem cells in adults.”
“Although it is really just a pipe dream at this point, it may be that augmenting this protective pathway against reactive oxygen might prove useful in enhancing longevity in tissues, or perhaps in entire organisms,” Gilliland noted.