Massachusetts General Hospital (MGH) researchers have a developed a totally new approach to treating liver failure - manipulating the immune response. If the results of the animal study can be applied in human patients, the approach may be able to keep patients alive until donor organs become available or to support liver function until the organ can regenerate itself, eliminating the need for a transplant. The findings are being reported in the journal PLOS One.

"We have identified a non-hepatic source of cells that can easily be expanded to the scale required for clinical application," says Martin Yarmush, MD, PhD, director of the Center for Engineering in Medicine at MGH, the paper's senior author. He also is the Helen Andrus Benedict Professor of Surgery and Bioengineering in the Harvard-MIT Division of Health Science and Technology (HST) and a senior scientific staff member at the Boston Shriners Burns Hospital.

The liver is one of the few major organs that is able to regenerate itself. But when the organ is damaged by diseases like chronic hepatitis, long-term alcohol consumption, or other causes, ongoing inflammation can increase cell death and suppress the natural regenerative process. The only current treatment for end-stage liver failure is transplantation, which is limited by the organ supply and requires long-term immunosuppressive treatment. While external liver assist devices have successfully supported some patients, such machines require a supply of preferably human liver cells, which have been difficult to acquire and expand.

For their investigation, the MGH research team used mesenchymal stem cells (MSCs) - cells from the bone marrow that develop into tissues supporting blood cell development in the marrow cavity. Previous research has shown that MSCs are able to inhibit several immune system activities. A supply of MSCs can be extracted from a patient's own marrow and expanded to levels that could be therapeutically useful. To evaluate the ability of human MSCs to treat organ failure involving inflammatory activity, the investigators tested several ways of using the cells to treat rats in which liver failure had been induced.

Several approaches to administering MSCs reduced the biological signs of liver failure and improved the animals' survival. Although simply transplanting MSCs was not effective, two methods of delivering molecules secreted by the cells lessened inflammation within the liver and halted cell death. Cycling the blood of rats with liver failure through an external bioreactor containing MSCs also greatly reduced the metabolic signs of liver failure in the animals. Even more significantly, 71 percent of the rats treated with the MSC-seeded bioreactor survived, while only 14 percent of those in a control group were alive one week later.

"One essential function of MSCs in the bone marrow is to secrete molecules that promote the growth and maturation of blood cells," say co-lead author Biju Parekkadan, an HST graduate student working in Yarmush's lab. "We are now finding that these same molecules can be used as potent immunotherapeutics and envision a multi-tiered treatment of liver failure based on this work. A patient presenting with liver failure could first be treated with an intravenous injection of an 'off-the-shelf' drug containing MSC-produced factors in an effort to halt cell damage and allow the organ to regenerate. If that is not effective, an MSC-based support device could be used as a bridge to transplantation or even as a long-term treatment."

The researchers note that exactly how MSC-produced molecules inhibit the movement of immune cells into a damaged organ is not yet known and is currently under investigation. They also hope to examine the possibility of combining both MSCs and liver cells in a potential support device and to test the potential of MSCs to treat other immunological diseases.

Additional co-authors of the PLOS ONE paper - all investigators in the MGH Center for Engineering in Medicine - are co-lead authors Daan van Poll, MD, and Kazuhiro Saganuma, MD; and co-authors Edward Carter, Francois Berthiaume, PhD, and Arno Tilles, MD. The work was supported by grants from the National Institutes of Health, Shriners Hospitals for Children, the National Science Foundation and the Michael van Vlooten Foundation.

Massachusetts General Hospital , established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.

Citation: Parekkadan B, van Poll D, Suganuma K, Carter EA, Berthiaume F, et al (2007) Mesenchymal Stem Cell-Derived Molecules Reverse Fulminant Hepatic Failure. PLoS ONE 2(9): e941. doi:10.1371/journal.pone.0000941
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