by Simone Alves
Improving engraftment increases survival in a mouse model
Drugs that encourage stem cells from the blood to engraft in the heart might be able to help prevent deaths caused by the tissue damage that occurs after heart attacks. A report published in Cell Stem Cell this month by Wolfgang Franz and colleagues at the Ludwig-Maximilians University in Munich suggests that targeting the SDF-1
–CXCR4 homing axis could save cardiac tissue and increase survival rates.
Although chemokines such as G-CSF can aid stem cell mobilization out of the bone marrow, says Franz, the main obstacle to using stem cells for therapy is that the cells don't home to the right place. SDF-1 is the major chemokine that attracts stem cells to damaged cardiac tissue. In its active form, SDF-1 binds to the CXCR4 receptor, which is expressed on many haematopoietic cells. To look at how this axis affects stem cell homing to the heart, the group targeted an enzyme called DPP-IV, which inactivates SDF-1, and created two different mouse models in which DPP-IV function was lost. "We wanted to stabilize the active form of SDF-1," explains Franz
In the absence of DPP-IV, bone marrow stem cells were more effective at homing to damaged tissue after simulated heart attacks in mice. The researchers examined multiple mouse models and found that the myocardium that contained the most CD45+/CD34+ stem cells derived from the blood in mice that lacked DPP-IV and were treated with G-CSF. (Also, the CD45+/CD34+ cells remaining in the peripheral blood were largely CXCR-4-, hinting that the receptor was involved in the migration; indeed, inhibiting CXCR-4 dramatically decreased stem cell migration.)
"What was really astonishing was the improved survival rate," says Franz. In fact, in the absence of DPP-IV function and plus treatment with G-CSF, mice that had sustained simulated heart attacks had a 70% chance of survival compared with 40% for cytokine-treated, wild-type mice. "We saw much less scar tissue, the ventricular walls were thicker, there was a reduction in apoptosis and there was improved vascularization," he adds.
The increased cardiac function and overall survival has already prompted a clinical trial in humans, which began in Munich last year. "There are different inhibitors for humans already on the market" says Franz. "Preclinical data is encouraging; the therapy is safe." The group hopes to publish the clinical data on the first 12 patients shortly.
The mouse study "is another potential step forward in the field", says Richard Burt, associate professor in the Division of Immunology at Northwestern University in Chicago. "In previous clinical studies, stem cells had to be collected and injected into the bloodstream, so this is an alternative, less invasive and less time consuming way to get cells to home to the heart."
Source: Nature