explore LSI
- Volume 3 Number 2
- Fall 2007
making a difference in human health through collaborative scientific discovery
Discoveries
From the Center for Stem Cell Biology
Widely held ideas about stem cells disputed
How do adult stem cells protect themselves from accumulating genetic mutations that can lead to cancer?
For more than three decades, many scientists have argued that the "immortal strand hypothesis"—which states that adult stem cells segregate their DNA in a non-random manner during cell division—explains it. And several recent reports have presented evidence backing the idea.
But in August 29 issue of the journal Nature, lead author Mark Kiel, Sean Morrison and their colleagues dealt a mortal blow to the immortal strand, at least as far as blood-forming stem cells are concerned.
They labeled DNA in blood-forming mouse stem cells and painstakingly tracked its movement through a series of cell divisions. In the end, they found no evidence that the cells use the immortal-strand mechanism to minimize potentially harmful genetic mutations.
A cluster of leukemia-forming cells from a mouse lacking the Pten gene. Blood-forming stem cells and leukemia-initiating cells differ in their dependence on Pten, and this difference can be used to selectively kill the cancerous cells without harming normal stem cells. (Photo by Omer Yilmaz, U-M Center for Stem Cell Biology.)
"This immortal strand idea has been floating around for a long time without being tested in stem cells that could be definitively identified. This paper demonstrates that it is not a general property of all stem cells," said Morrison, director of the Center for Stem Cell Biology.
It remains possible that stem cells in other tissues use this process.
"We've been able to show that this is not a mechanism by which blood-forming stem cells reduce their risk of turning into cancer and, presumably, we should be looking elsewhere to understand what those mechanisms really are," he said.
Stem cells generate all of the tissues in the developing human body, and later in life provide replacement cells when adult tissues are damaged or wear out.
LSI team identifies gene that regulates blood-forming fetal stem cells
In the rancorous public debate over federal research funding, stem cells are generally assigned to one of two categories: embryonic or adult. But that's a false dichotomy and an oversimplification. A new study led by LSI's Sean Morrison adds to mounting evidence that stem cells in the developing fetus are distinct from both embryonic and adult stem cells.
In the last several years, stem cell researchers have realized that fetal stem cells comprise a separate class. They recognized, for example, that fetal blood-forming stem cells in umbilical cord blood behave differently than adult blood-forming stem cells after transplantation into patients.
A team led by Sean Morrison has identified the first known gene, Sox17, required for the maintenance of blood-forming stem cells in fetal mice, but not in adult mice. The discovery provides a critical insight into the mechanisms that distinguish fetal blood-forming stem cells from their adult counterparts.
The findings could also lead to a deeper understanding of diseases such as childhood leukemias. Childhood leukemias are cancers that afflict blood-forming cells and hijack normal stem cell self-renewal mechanisms.
"One of the next questions in our cross hairs is whether Sox17 gets inappropriately activated in certain childhood leukemias—and that's an idea that nobody had in their mind before this work," Morrison said. "If it's true, it'll give us a new target for cancer."
The Sox17 results appeared online July 26, 2007 in the journal Cell. U-M's Injune Kim is lead author of the paper; Morrison and U-M's Thomas Saunders are co-authors.
"Identification of Sox17 could also facilitate efforts to form blood-forming stem cells from human embryonic stem cells, a goal that could enhance bone marrow transplantation," Kim said.
The Sox 17 study is part of a larger, ongoing U-M effort to understand how stem cells are regulated at different stages of life. Last September, Morrison's team reported that old stem cells don't simply wear out; a gene called Ink4a actively shuts them down.
"Each time we identify one of these genes, we get a new insight into what stem cells really are, what regulates their identity and how their age-specific functions work," Morrison said. That information could lead to new treatments for degenerative diseases.