Identifying the mechanisms that control cell life span is one of the more important questions facing stem cell researchers, indeed, all researchers attempting to understand normal and abnormal cell and organ development. So the recent discovery by a Harvard Stem Cell Institute team that a family of well-known transcription factors plays a major role in regulating the life span and longevity of hematopoietic, or blood, stem cells is of particular note. Transcription factors are proteins that participate in the synthesis of RNA using a DNA template.
Gary Gilliland, director of Harvard Stem Cell Institute’s (HSCI) Cancer Stem Cell Program, and colleagues at Brigham and Women’s Hospital and the Dana-Farber Cancer Institute believe that their findings may have broad implications for stem cells in other tissue types as well, and may eventually lead to strategies to increase cell longevity.
It is possible, the researchers say, that their findings could eventually lead to ways to enhance the blood stem cells that are at the heart of the bone marrow transplants used to treat leukemia.
Gilliland, a professor of medicine at Harvard Medical School (HMS) and a Howard Hughes Medical Institute investigator, said that the recent findings from his lab and Ronald A. DePinho’s lab at Dana-Farber “have important implications for normal stem cell biology, and for cancer stem cells.
“In brief, we have shown that a highly redundant family of transcription factors, FoxO, is required for regulation of longevity and life span of normal adult hematopoietic stem cells. Furthermore,” said Gilliland, “the critical effectors of FoxO function are genes that regulate response to reactive oxygen species – these findings thus have important implications for strategies that might seek to modulate longevity of adult tissue stem cells.”
Zuzana Tothova, an HMS graduate student in Gilliland’s lab and the lead author of the report on the work in the journal Cell, said that when three types of Fox0 genes were switched off, the life span of the hematopoietic stem cells was sharply reduced. In an accompanying Cell paper, a group lead by DePinho, an HMS professor of medicine, reported that the FoxO genes also have tumor suppressor functions.
Tothova said that the findings of both groups of researchers add to the understanding of the molecular mechanisms limiting the life span of blood stem cells. And understanding the mechanisms limiting the life span is essential to finding ways to increase it.
Gilliland explained that the findings indicate that the FoxO proteins “play essential roles in the response to physiologic stress related to oxidation,” which has implications in other types of tissues. It might conceivably be possible, he said, to increase cellular longevity by findings ways to protect the cells against the effect of reactive oxygen.