Stem Cells Hit Reverse
A transcription factor can make adult stem cells behave like fetal stem cells.
A transcription factor that is usually only expressed in fetal stem cells can make adult blood stem cells act like their younger counterparts, according to a new study published today (July 31) in Genes and Development. The findings hold promise for treating leukemia by converting cancerous adult stem cells, which are driven by pro-cancer growth signals, into fetal stem cells, which don’t respond to those signals.
“This is a fascinating paper that turns back the clock on hematopoietic stem cells,” said George Daley, a stem cell biologist at Children’s Hospital in Boston, who was not involved in the study. “This is highly significant for understanding how aged blood cells might be rejuvenated and adds to a growing literature that teaches us that we can alter the fate of cells by reprogramming them.”
While adult stem cells divide occasionally, fetal stem cells are able to renew themselves indefinitely, and fetal stem cells differentiate into different ratios of cell types. Previously, researchers had mapped out the mechanisms that regulate the fate of stem cells of different ages, but no one had yet determined what chemical signals dictate behavior in fetal hematopoietic stem cells, which form the blood.
In 2007, University of Michigan, Ann Arbor, stem cell biologist Sean Morrison and his colleagues showed that a transcription factor called Sox17 was turned on in fetal, but not adult, stem cells. That raised an intriguing question, Morrison said: “If you turn Sox17 back on in the adult cells, do you confer fetal stem cell properties in those cells?”
To find out, the researchers infected adult stem cells with a retrovirus that carried Sox17. Adult stem cells that expressed Sox17 regained the ability to self-renew. They also formed more red blood cells and fewer lymphocytes—a ratio similar to that seen in fetal development. The adult stem cells also began expressing receptors only found in fetal stem cells.
The findings suggest that a few master transcriptional regulators determine the fate of blood stem cells. Manipulating them could one day help renew aging blood stem cells, which may help treat anemia, poor vaccine response, and tumor formation in the elderly. It could also allow scientists to attack leukemia by transiently converting cancerous adult blood stem cells into fetal, as the signals fueling growth in adult leukemia cells are not present in fetal stem cells, Morrison said.
But the rejuvenated adult stem cells weren’t identical to their fetal counterparts. For instance, in unpublished follow-up studies, Morrison and his colleagues found that the adult bone marrow didn’t make B and T cells that are usually only made in fetal development. In addition, when Sox17 was turned on too long, the adult stem cells morphed into leukemia cells. The researchers suspect that turning on Sox17 in cells that don’t normally express it somehow fueled cancer-promoting mutations, suggesting a potential limitation to using Sox17 to treat leukemia.
S. He et Al., “Sox17 expression confers self-renewal potential and fetal stem cell characteristics upon adult hematopoietic progenitors,” Genes and Development, doi/10.1101/gad.2052911, 2011.
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