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Stanford Report, November 20, 2002

Researchers track stem cells in the act of morphing

By AMY ADAMS

Researchers at the medical center have tracked the path of bone marrow stem cells as they transform into an adult tissue. This work, published in the Nov. 15 issue of the journal Cell, marks the first time scientists have seen the progress step by step.

In previous work, researchers including Helen Blau, PhD, the Donald E. and Delia B. Baxter professor of pharmacology, have seen injected bone marrow cells integrate into the muscles, livers and brains of mice. But until now, they have not witnessed the sequence of events that leads to this transformation.

Helen Blau and graduate student Mark LaBarge study bone marrow cells, which appear to transform into muscle cells in laboratory mice. Their work backs up the concept of stem cell plasticity. PHOTO: AMY ADAMS

In their Cell paper, Blau and graduate student Mark LaBarge describe how they saw transplanted bone marrow cells first locate to the muscle as a muscle-specific stem cell called a satellite cell. These former bone marrow cells lurked in the muscle until exercise-induced muscle damage signaled them to help repair the injury by fusing with existing muscle cells.

"These studies are the first to show that sequential, injury-related events send cues that recruit the cells from the bone marrow," Blau said. "This appears to be a mechanism for replenishing lost tissue-specific stem cells with bone marrow cells that can perform their function."

The research is a first attempt to learn how bone marrow stem cells incorporate into muscle, tracing the pathway the cells follow. The researchers first gave whole-body irradiation to a group of mice to destroy bone marrow cells. They then injected bone marrow taken from genetically altered mice that make a green fluorescent protein in all of their cells. These injected cells eventually repopulated the recipient’s bone marrow, where they produced green fluorescent blood and immune cells.

The process of irradiating the mice to destroy bone marrow also reduced the number of satellite cells that dot the muscle fibers. Within two to six months after receiving the new bone marrow, the recipient mice had satellite cells that made green fluorescent protein — something that could occur only if those satellite cells had come from the injected bone marrow.

The question was whether these newly formed satellite cells could walk the walk and talk the talk of satellite cells. They looked normal, but could they fulfill the satellite cell’s role of repairing damaged muscle fibers? In searching for an answer, LaBarge put one group of mice on a muscle-damaging training regimen while their littermates remained sedentary. At the end of six months, LaBarge found the same number of green fluorescent satellite cells in both groups of mice. However, the fit mice had 20 times the number of muscle fibers with green fluorescent protein compared with their cage-potato littermates.

"This paper shows that stem cell conversion is damage-related," Blau said. "First the bone marrow cells take up residence as tissue-specific stem cells and after damage they participate in the muscle fibers." She added that individual bone marrow cells switch fates to become satellite cells, rather than fusing with existing satellite cells as had been speculated in the past.

Blau’s paper comes amidst controversy among stem cell researchers about the nature of adult stem cells. Recent papers have found that the same bone marrow stem cells that repopulate the bone marrow after transplantation cannot form other cell types. Blau points out that in the current experiment LaBarge injected whole bone marrow — bone marrow that contains the stem cells that can reform bone marrow in addition to a host of other cell types.

The cells that she and LaBarge witnessed in the act of forming satellite and muscle cells could be any one of the many different types of cells present in the bone marrow. Blau also added that the other recent studies did not test the role of tissue injury in recruiting bone marrow stem cells.

"Next we need to find out which cells are going to the muscle," Blau said. "We’re very open-minded about what that cell may be." Blau said the research could pave the way to a new method of administering drugs. "If we can get efficient uptake, these cells could be used for gene delivery," she said.

For example, if she could inject bone marrow cells that make a protein that’s lacking in a muscular disease, those cells could integrate with the muscle, provide the lacking protein and potentially treat the disease.

While she sees therapeutic potential in adult stem cells, Blau said researchers need to explore both adult and embryonic stem cells. "Different diseases may benefit from treatment with different cell types," she said. She added, however, that adult stem cells have unique advantages. "The Holy Grail would be if adult stem cells can be recruited to specific tissues, then this approach could be used to enlist the body to fight its own disease."



Baxter lab opens its doors onto medical research (5/22/02)

Debate over stem cells is local as well as national (9/11/02)