Credit: Sebastian Kaulitzki

Using a new approach to immunomodulation, researchers at Massachusetts General Hospital (Boston) have developed two practical methods for treating acute liver failure in rats.

Fulminant hepatic failure is associated with a local and systemic immune response that interferes with the liver's ability to repair itself. Attenuating this immune response could enable patients with liver failure to survive until a donor organ is available, and may even provide enough support to allow the liver to regenerate, eliminating the need for a transplant. In previous studies, Martin L. Yarmush and colleagues successfully used immunomodulation to treat rats with liver failure but sought a clinically viable approach. Now they achieve a similar effect using human bone marrow mesenchymal stem cells (MSCs), which have been shown to inhibit immune cell function.

The researchers induced liver failure in rats using a hepatotoxin and assessed various MSC treatment modalities (PLoS ONE 9, e941; 2007). Though direct transplantation of MSCs was not effective, intravenous injections of MSC cellular lysates had a distinct survival benefit, as did injection of a conditioned medium of MSC-derived molecules. Reduction in mortality was dependent on cell mass and had an optimum: benefit diminished when the number of cells was raised beyond a certain point, indicating a therapeutic window of efficacy.

Cycling rats' blood through an extracorporeal bioreactor containing MSCs was also effective: 71% of rats treated with the MSC-seeded bioreactor were still alive a week later, whereas only 14% of those in control groups survived. Such external liver assist devices have previously shown promising results but are so far not practical for routine use because they require a supply of functionally stable human liver cells, which are difficult to acquire and maintain outside the body. Using MSCs in these devices may eliminate the need for human hepatocytes. Moreover, the observation that human MSCs were effective in rats suggests that the treatments can cross species barriers.

More investigation is needed to establish whether MSC treatment is applicable to humans. “Ideally, we have developed two clinically relevant treatment strategies that could be employed individually or in tandem,” Yarmush tells Lab Animal. “In the acute setting, a patient presenting with [fulminant hepatic failure] could be treated with injections of MSC molecules as an 'off-the-shelf' product. If the damage is too extensive, a patient can be supported by an extracorporeal bioreactor as a curative treatment or as a bridge to transplantation.”