How stem cells find their way around

Harvard Stem Cell Institute (HSCI) researchers have for the first time identified in mice a cellular mechanism that directs stem cells to their ultimate destination in the body.

The finding in blood stem cells by HSCI co-director David Scadden and colleagues holds the promise of greatly increasing the efficiency of the bone marrow transplants used to treat various forms of cancer and has enormous implications for future therapies utilizing all forms of stem cells.

“Figuring out the mechanisms that tell stem cells how to get to where they need to go is a major problem when we’re thinking about stem cell therapies,” said Scadden, who is the director of the Center for Regenerative Medicine at Massachusetts General Hospital and is also the co-chairman of Harvard’s new Department of Stem Cell and Regenerative Biology.

Hal Broxmeyer, chairman and Mary Margaret Walther Professor of Microbiology/Immunology and scientific director of the Walther Oncology Center at Indiana University School of Medicine, said the new study “provides crucial, important, and physiologically relevant information on [blood stem cells’] homing/engrafting capability … Most importantly, the results from this study open up the possibility of using a relatively simple means to enhance homing/engraftment and mobilization of” blood stem cells in bone marrow transplantation. “… I look forward with great anticipation to seeing this work by Scadden’s group successfully translated into the clinic for patients,” Broxmeyer said.

Scadden, a physician-scientist who specializes in the treatment of cancers of the blood system, notes that the “system has paved the way for so much of our understandings of stem cell therapy.” Bone marrow transplantation, which has been used for several decades to treat a number of cancers, is essentially stem cell therapy, as the donated marrow transplanted into the patient carries blood stem cells that it is hoped will provide the patient with a new blood-producing system.

In this new study, published today in the journal Nature, Scadden’s team reports identifying the cellular pathway — the route by which signals travel from receptors on the cell’s surface to direct the action of the cell — that serves as a kind of GPS directing the travel of the cell. Additionally, the researchers report a number of already approved drugs — used to treat a variety of diseases — that activate this directional system.

“This is a pathway that’s been intensively studied because of its relationship to hormone function and blood pressure,” Scadden explained. “There is a wide range of drugs that have been developed that effect this pathway, for everything from blood pressure regulation to asthma control.

“This is a critical pathway in a number of cells,” Scadden continued. “It’s important in the heart and the blood vessels, in the brain, and in platelets. We found out not only that it’s there, but that it’s absolutely critical for stem cells to find their way home. And if you stimulate it,” he said, “you can improve the cell’s path-finding ability.”

Serendipitously, another group of HSCI researchers, led by Leonard Zon at Children’s Hospital Boston, has approval from the U.S. Food and Drug Administration to begin a clinical trial seeking to improve the efficacy of bone marrow transplantation, using a compound that activates the pathway identified by the Scadden group — prostaglandin E2.

“Ours was a mechanistic study,” said Scadden, one in which he and his colleagues sought to find the mechanism that directs stem cells to where they belong and can best multiply. Meanwhile, he said, Zon and colleagues approached the problem from another direction. “Len was saying, ‘I’m going to test every drug that’s known on blood stem cells in zebra fish [the system in which Zon does his research]’ and he found one that activates this pathway,” publishing that work in Nature just about two years ago.