More than one type of adult stem cell seems to exist in the intestine, something that's likely true of other organs as well. And while that means using adult stem cells to treat disease is likely more complicated than previously believed, understanding it likely offers great opportunity to fine-tune approaches for better success, according to Utah's Nobel laureate and research from his laboratory at the University of Utah.

Mario Capecchi likens the surprise finding to scouting the opposing team before an important football game.

"When you know nothing about the other team, anything can happen. Knowing more, even though it's more complicated, means you're better situated to make whatever you want it to do work," said Capecchi, who shared the 2007 Nobel Prize for Medicine or Physics with two other researchers.

The U. findings were published Sunday online in the journal Nature Genetics.

Capecchi and geneticist Eugenio Sangiorgi used a molecular marker called Bmi1 to label stem cells in the small intestine of mice. Cells in the intestine by necessity wear out fast, in two to five days. "It's an awful environment, you stuff all that food into it and it's breaking it down," said Capecchi, co-chair and distinguished professor of human genetics at the U. and an investigator with the Howard Hughes Medical Institute. He said if cells didn't turn over quickly, tissue wouldn't survive.

Embryonic stem cells, which have been controversial, can become any kind of cell within the body. Adult stem cells can give rise to any type of cell within a particular organ and don't carry the political baggage, so researchers have pinned a lot of hope on using them to repair damaged organs, such as injecting stem cells to fix a heart after a heart attack or using pancreatic stem cells to cure someone who is diabetic.

The U. researchers had to prove two traits to show they were dealing with stem cells: the ability to renew themselves and the ability to give rise to all the different kinds of cells that make up an intestine. By using Bmi1, which turned the cells blue under the microscope, they could follow those cells and what they became to prove those two traits were true, he said. The presence of cells with the marker over time shows they self renew. And the fact that the colored marker could be found in all types of cells showed they gave rise to different types of cells.

Capecchi and Sangiorgi, a postdoctoral fellow in human genetics, thought the entire intestine would have the marked blue cells but found high quantities only in the first third of the intestine.

The intestine is a complicated organ, doing different things at once. It's absorbing some things (such as nutrients) and excreting others, all in a "highly orchestrated" fashion, Capecchi said. The indication is that stem cells at various positions, slightly different from each other, give rise to the needed cells quickly.

He said a group of researchers in the Netherlands, using similar technology, found a different marker than Bmi1 to label stem cells in the intestine. The organ has been well studied, but until recently there was no ability to look at a genetic level since there were no molecular markers. Some have believed the stem cells are located in a crypt at the bottom of the intestine, while others believed they are in a crypt at the top. The U. and Netherlands researchers made opposite findings.

Some researchers have said stem cells proliferate and replicate, then the progenitor cells start migrating up the villi, changing into different kinds of cells to create the various properties of the intestine. Others have argued they march down from a crypt at the top.

The U. researchers found 95 percent of the time the stem cells are at the top, while the Dutch researchers found 95 percent at the bottom.

"I think we're both right. I think we're labeling the stem cells at different phases of what they're doing," said Capecchi.

Each time a stem cell replicates, it makes two daughter cells and "sometimes they're not going to be perfect, leading to mutations" in DNA, he said. More replication means more potential for mistakes. So while one of the two copies replicates over and over then dies, the other sits quietly, a kind of backup to ensure the genome doesn't accumulate a lot of mutations, he said.

"I think we're seeing two populations of stem cells. We're putting labels in the cells that are setting aside and he's labeling those that are replicating," indicated by the fact that in the Netherlands research, the color label is getting into its progeny faster than it's happening in the U. research. "Ours are the more quiescent."

That also indicates to Capecchi that the cell's location controls what's happening and whether one is waiting or replicating. The cells, he says, seem to migrate back and forth.


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