In many cases, the trauma induced by acute myocardial infarction (AMI) triggers a nearly irreversible process ending in heart failure. While current regenerative therapeutic strategies aimed at treating such cardiac damage involve harvesting stem cells, a new study in the journal Nature Biotechnology proposes an alternative solution—one that makes the body do most of the work.
In the article, scientists from the Karolinska Institutet and Harvard University detail a way to stimulate cardiovascular regeneration by expressing a growth factor in the heart that directs native cells to promote vascularization after injury to the organ. The researchers successfully introduced their therapy to the hearts of mice up to 48 hours after cardiac injury and observed the regenerative effects for up to a year.
“What you are doing here is making an acute change in the long-term outcome by having a very short one-time effect,” explained Kenneth Chien, professor in the Department of Cell and Molecular Biology and the Department of Medicine at the Karolinska Institutet and visiting professor in the Department of Stem Cell and Regenerative Biology at Harvard University, who led the study. “They’re getting [treated] right after the initial event and then we are changing the trajectory, so it’s an acute treatment for an acute event rather than a chronic treatment for an acute event.”
Chien’s team utilized a growth factor for vascular endothelial cells in the heart known as VEGF-A (vascular endothelial growth factor-A), which also acts as a pivotal signaling protein for vascularization. By expressing VEGF-A in mice, the team could effectively “switch” the role of the heart’s local progenitor cells that normally build cardiac muscle into builders of coronary vessels, thus promoting angiogenesis.
“These epicardial progenitors normally contribute to the scar tissue in the heart, so we thought that maybe [VEGF-A] would amplify them and change their mind to become vessels,” explained Chien. And this was exactly what happened. “So it’s kind of a ‘twofer’…you decrease the amount of fibrosis in the heart and increase the vascularization.”
In order to amplify VEGF-A expression without triggering an antiviral immune response, Chien’s team injected a synthetic modified RNA (modRNA) encoding VEGF-A into the hearts of mice 24-48 hours after infarction. They then tracked the mobilization of the progenitor cells using lineage tracing and tagged the epicardium on the surface of the heart using a CRE recombinase gel. In the end, the group found improved heart function and enhanced long-term survival after a single pulse of the VEGF-A modRNA to the exact location of the progenitor cells. “I think this suggests a new paradigm in regenerative therapeutics,” said Chien. “The organ itself may mobilize a few rare progenitors, and if you hit them with the right signal at a high enough level at a specific time and place, then you might be able to exert a long-term change in how much end injury exists after the acute stimulus.”
While Chien and his team are encouraged by the results, he also believes there is much to do before their findings can be translated to the clinic.
“It’s just a mouse model, so we need to do this in larger animals,” notes Chien. “The mouse has not always been predictive of larger animals, but this has been a phenomena where we have already been able to show that larger animals can take up and express the modified RNA.”
“These are still early days but I think that this has a good chance to go the full distance.”
Zangi L, et al. “Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction.” Nature Biotechnology, doi:10.1038/nbt.2682