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Setting the Stage for Personalized Medicine
Novel Findings on Engraftment of Stem Cells in Models of Acute Lung Injury

"Our overall goal is to elaborate new therapies for acute lung injury, including bacterial pneumonia, using different types of stem cells," explains Dr. Serikov.

Novel Findings on Engraftment of Stem Cells in Models of Acute Lung Injury
CHORI principle investigator, Vladimir Serikov, PhD, is on a mission, exploring the pathogenesis and possible future clinical impact of stem cells on a variety of different pre-clinical models of acute lung injury.

As with any meaningful effort, the endgame can't be achieved in a single study, but by one step at time. Dr. Serikov's latest publication in Lung, investigates the pathogenesis of stem cell involvement in the lung recovering from injury in order to further understand the mechanisms by which stem cells confer a positive therapeutic benefit.

Several prior studies from other labs have claimed that bone-marrow derived cells (BMDC) participate in recovery of tissue by moving to the site of injury and transforming into functional cells. Dr. Serikov's latest study, however, suggests things are not quite so simple.

"In contrast to these previous results, we were unable to confirm that the BMDC turn into functioning epithelial or endothelial cells," says Dr. Serikov. "Things are much more complex than one would realistically or optimistically imagine."

Dr. Serikov's study was a first in important ways. Unlike previous study models, which used oxidative injury to the lung, Dr. Serikov used a bacterial pneumonia model, providing first-time data that mimics more closely the real clinical world.
"Oxidative lung injury, which most of the previous studies use as a model, is extremely rare in clinical practice, whereas our model is very close to what you would find in real situations, in which most pneumonias are caused by bacterial infection."
Similarly, the radiation doses given in the previous studies in order to transplant animals with foreign bone marrow were far more lethal than could ever be achieved clinically.

"Our doses were much lower as well, so in that sense, this study is unique in that it uses realistic models as close as possible to what you would find in a clinical situation," says Dr. Serikov.

While Dr. Serikov's model provides conclusive evidence that long-term engraftment does not occur on physiologically relevant scale, the results did demonstrate the presence of BMDC in the lung during a temporary period of time at the peak of acute inflammation from bacterial pneumonia, suggesting a temporary and possibly regulatory role after infection. Such a phenomenon could be in keeping with results from previous studies in which positive experimental results were identified, but in the absence of cell engraftment.

As reported in an August 2007 publication in the Journal of Immunology, in which Dr. Serikov collaborated with Michael Matthay, MD, of the University of California at San Francisco, while stem cells did not engraft in the lungs of
mice with acute lung injury, there was a two-fold beneficial effect on survival when mice were exposed to intrapulmonary administration of BMDC.

"This is a significant indication that these cells are potent in terms of the therapeutic treatment of acute lung injury," says Dr. Serikov.

So while the mechanisms of how cell transplantation works need further elucidation, the pursuit of the end goal - better treatment options for patients with lung injury - is still in sight, as the clinical benefit is no less apparent.

"How stem cells work following transplantation to the site of injury still remains a mystery. It's clearly not as straightforward and simple as stem cells simply going to the site of injury and very easily replacing the damaged tissue," says Dr. Serikov.

"Our hypothesis, though were are still in the process of proving it, is that instead stem cells produce an immuno-modulatory effect at the site of inflammation, thus decreasing the extent of that inflammation."

Dr. Serikov expects to publish data regarding this hypothesis later in the year, but in the mean time studies are currently planned to extend the intrapulmonary BMDC studies to a bacterial pneumonia model like the one used in this study. In addition, Dr. Serikov hopes to pursue funding to start a clinical trial as well.

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Tuesday, May 17, 2011 8:19 AM

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