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Coaxing Cells to Become Liver

When Saul Sharkis, Ph.D., professor of oncology at the Johns Hopkins Kimmel Cancer Center, started studying stem cells in bone marrow in the 1980s, he didn’t really know what they looked like. He did know that they were scarce. “Imagine a room filled with blue tennis balls,” he says, “and you need to find the one red ball. If you’re lucky it’s sitting in front of the door, but more likely it’s not. How are you going to find that ball? That’s what we were up against.”

He and colleague Rick Jones, M.D., also of the Johns Hopkins Cancer Center, devised a way to isolate stem cells from bone marrow based on how they look and behave. “It was like looking for a needle in a haystack,” Sharkis says, “but now we’ve been isolating these cells twice a week for the last 20 years. What we still don’t know is how to kick-start stem cells into differentiation.”

In 2000, a student in the lab looking through old autopsy files from bone marrow transplant patients found that some female patients who had received marrow from male donors had male cells in their liver. This suggested that transplanted bone marrow cells had somehow found their way into the liver and differentiated into functional liver cells.

Sharkis and his team decided to test this in mice by performing bone marrow transplants—male marrow into female mice—and examining the liver and other tissues. They found male cells by looking for the presence of Y chromosomes in lungs, intestines and liver.

“There were two possible things happening here,” explains Sharkis. “Either the transplanted cells were fusing with liver cells or they were differentiating and really populating these tissues.”

To figure out which was happening, the researchers grew bone marrow stem cells in a dish with liver cells but kept the two cell types separated by a filter so fine that cells could not pass through. By virtue of sheer proximity, the bone marrow stem cells started making proteins found only in liver cells.

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Sharkis’ team, led by Yoon Young Jang, M.D., Ph.D., now an assistant professor of oncology at the Johns Hopkins Cancer Center, then isolated bone marrow stem cells from male mice and transplanted them into female mice with damaged livers.

As it turns out, the research team found that transplanted bone marrow cells were differentiating into liver cells. How are they doing that? “We’re now in the process of doing the biochemistry needed to identify the factors being put out there by the damaged liver,” Sharkis says.

He and his team now are interested to see if bone marrow-derived stem cells can repopulate other tissues damaged by disease, like the pancreas and kidneys.

Says Sharkis, “We’re not quite ready for prime time yet, but we’re studying biology in real time and that’s really rewarding.”

--By Audrey Huang