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Stem Cells: Full of Potential

Human stem cells can do it all, differentiating themselves into every kind of muscle, blood, bone and organ. The trick is to make them do that on command, to create models of disease or even to grow replacement parts.

By Lauren Ware // The MGH Research Issue 2011
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stem cells

Adam Voorhes for Proto

Stem cells are to medicine what transistors were to electronics,” says David Scadden, a hematologist-oncologist who directs the Massachusetts General Hospital Center for Regenerative Medicine in Boston. “We don’t really know all the ways they will have an impact, but they definitely have an extremely powerful potential.”

Unique because they can differentiate into virtually any cell type, stem cells are teaching us about normal cell development and how it can go awry. They give researchers a tool to create cells afflicted with a specific disease that can then be used to test drugs. And—perhaps most tantalizing—they may become a source of healthy cells and tissues to treat conditions as varied as Parkinson’s disease, osteoarthritis, heart disease and spinal cord injury. Work with stem cells is an important area of molecular biology, a burgeoning field that traces physiological processes to activities within and among cells.

The Center for Regenerative Medicine includes physician-scientists and other researchers who work in close collaboration with the Harvard Stem Cell Institute. Scadden’s laboratory studies blood stem cells, including malignant versions implicated in leukemia. His aim is to figure out how to give normal stem cells a competitive advantage over cancerous ones during leukemia treatments. “In leukemia and possibly in other cancers as well, there is a battle going on between normal stem cells and cancerous stem cells,” Scadden says. “One or the other ultimately wins. Sometimes we can use chemotherapy to knock down both kinds, and the normal cell will prevail. But that’s relatively rare, and we’d like to make it more common. We’d like to provide an advantage to the normal cells.”

Scadden and his colleagues have discovered that stem cells exist in a “neighborhood” of cells, and that disturbing just one cell affects the integrity of the entire group. Other scientists at the Center for Regenerative Medicine are studying how to use stem cells and three-dimensional organ scaffolds made of proteins to generate entire replacement organs; how neural stem cells differentiate into the many types of neurons that populate the brain, including those involved in ALS and spinal cord injuries; and how cell fate is determined on the most fundamental level during development.

In another aspect of the stem cell effort, Kenneth Chien, director of the MGH Cardiovascular Research Center, and his colleagues are studying how the human heart develops from stem cells. “The heart is a mosaic of cell types,” Chien says. “Among them are the ventricular muscle that makes up the heart itself, smooth muscle that forms blood vessels in the heart, and endothelial cells that line the heart. Our questions involve how all of this complexity arose and what pathways guide its development.”

In trying to answer those questions, Chien found a master heart stem cell—a progenitor cell—that can give rise to nearly all the distinct cell types that make up the heart. His laboratory was able to isolate, purify and clone human master progenitor cells from embryonic stem cells and generate the three lineages of heart cells: smooth muscle, ventricular muscle and endothelial tissue.

In 2009, Chien’s laboratory took this work one step further by making a fully functioning strip of heart muscle tissue from embryonic stem cells. Now the laboratory is trying to use its expanding understanding of how the human heart develops to find out how to repair heart tissue after a heart attack or in infants born with congenital heart disease. The scientists have found evidence suggesting that there may be a very small number of master progenitor cells still present in the adult heart. “If you can deliver a developmental signal to those cells, it’s possible they will be mobilized to start rebuilding components of the damaged heart,” Chien says.

Konrad Hochedlinger, a biologist at MGH, also studies stem cells, manipulating mature, differentiated cells (taken from skin or other tissue) so that they return to an embryonic state. That approach has its origins in a study done at Kyoto University in Japan by Shinya Yamanaka (who, with MGH biologist Rudolf Jaenisch, shared MGH’s 2011 Warren Triennial Prize for work with iPS cells). In Yamanaka’s work, reported in 2006, scientists used a virus to insert a few genes into adult cells that transformed them into stem cells. Known as induced pluripotent stem, or iPS, cells, they may be able to provide a source of stem cells that avoids the controversial destruction of human embryos. What’s more, iPS cells hold the possibility of doing things embryonic cells can’t. For example, scientists might be able to take the skin cells of a patient with Parkinson’s disease, turn them into iPS cells, and then steer them to become the types of neurons that are affected in Parkinson’s. That could provide a “disease in a petri dish”—a human-cell model that might be used to study the disease’s biological pathways as well as to test possible treatments.

Hochedlinger’s laboratory is also developing potentially less dangerous iPS cells. The virus that was used to introduce genes into the first iPS cells integrated itself permanently into the genetic makeup of the recipient—a development that can damage existing genes and might cause cancer. The laboratory now uses an adenovirus—basically the common cold virus—to shuttle the genes into the cell, since the virus vanishes once it has transferred the genes it carries.

The other potential application of iPS cells is stem cell therapy. Instead of transplanting a liver, for instance, requiring a patient to live with the side effects of powerful immunosuppressant drugs, “physicians could make patient-specific stem cells, perhaps generating liver cells to repair the damage and transplanting them into the body,” says Hochedlinger. “There is data from animal studies showing it’s feasible to treat Parkinson’s disease and sickle cell anemia through this approach, but for safety reasons it hasn’t been done in humans yet.” He estimates that human applications of this research are probably 5 to 10 years ahead, while other aspects of the widespread work with stem cells could take much longer to reach fruition. Yet if the results even begin to fulfill the very high hopes for this branch of medical research, it will have been worth the wait.

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The Other Stem Cells

Konrad Hochedlinger

Once considered mere substitutes for embryonic cells, re-engineered adult cells are making breakthroughs of their own.

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