Cardiac Progenitor Cells: The World First Embryonic Stem Cell Heart Trial
The world’s first trial using cardiac progenitor cells derived from human embryonic stem cells represents a landmark moment in cardiovascular medicine. This long awaited trial comes after extensive preclinical work on more than 350 rats, 50 immunodeficient mice, and 32 non human primates.
“After 20 years in the stem cell area and a daily practice of cardiac surgery, I am very cautiously optimistic,” said Principal Investigator Philippe Menasche, chief of the Heart Failure Surgery Unit of the Hôpital Européen Georges Pompidou and director of an INSERM lab devoted to cell therapy of cardiovascular diseases.
How the Cardiac Progenitor Cells Trial Works
The world first trial gives cardiac progenitor cells made in a laboratory from human embryonic stem cells to six patients. Specifically, patients receive purified CD15+ Isl 1+ cardiac progenitors in a biocompatible fibrin gel patch, which is attached to the infarcted — or damaged — portion of their hearts to anchor the cells.
A pericardial flap made of autologous cells from the patients covers the patch, providing trophic factors to the embryonic stem cell progenitors. Patients receive the cardiac progenitor cells during scheduled coronary artery bypass or mitral valve procedures.
Earlier, Menasche’s team established that their embryonic stem cell progenitors, once implanted in animal hearts, could differentiate into cardiomyocytes that improve left ventricle heart function without causing teratomas — tumors that represent a key safety concern in stem cell research.
How the cells work “remains elusive,” Menasche noted. There is no proof yet that the cardiac progenitor cells themselves remuscularize or become heart muscle. Rather, they may act as natural factories, releasing healing trophic factors that stimulate the heart’s own repair pathways.
An Alternative Approach: Direct Injection
At a meeting of the New York Stem Cell Foundation, University of Washington cardiologist Chuck Murry presented an alternative approach. His research showed that more mature cardiomyocytes from embryonic stem cells can form new cardiac muscle when injected directly into monkey hearts after myocardial infarction.
Murry’s human embryonic stem cell derived cardiomyocytes formed large grafts of human myocardium averaging 40 percent of the size of the monkey heart infarcts, with electromechanical integration confirmed by histology revealing gap junctions coupling graft and host tissue.
However, a significant problem emerged: his more invasive injections resulted in ventricular arrhythmias in all monkey hearts receiving the cells. The arrhythmias lasted two to three weeks, then subsided — but they represent a meaningful safety concern before proceeding to human patients.
“Menasche’s group is taking a different approach,” Murry told Bioscience Technology. “They are putting a sheet of cardiovascular progenitors atop the surface of the heart, while we are doing direct injection into the wall. We’ve found that putting cells on the heart’s surface results in a scar tissue barrier that prevents them from integrating electrically. No electrical integration, no arrhythmias.”
The Trade Off Between Safety and Efficacy
Menasche acknowledged the apparent trade off between the two approaches. His cardiac progenitor cells are delivered via epicardial patch — earlier stage cells in lower quantities — compared to Murry’s direct injection of more mature cardiomyocytes in larger numbers.
Preclinical data suggest the patch approach may be less arrhythmogenic than injections, which create multiple intramyocardial clusters that can slow electrical impulses and set the stage for arrhythmias. However, Menasche noted this will need to be validated clinically — which is why all patients in the cardiac progenitor cells trial will be fitted with an implantable cardioverter defibrillator to record all possible arrhythmic events.
“The prevailing hypothesis is that the cells do not predominantly act by generating new tissue by themselves, but rather by harnessing endogenous repair pathways through the release of various factors,” Menasche said. “If such is the case, diffusion of the factors from the patch acting as a carrier should work. At least, we hope so.”
Still Learning
Both Murry and Menasche stressed that while their teams have put exhaustive work into embryonic stem cell research, there is still much to learn. Murry established function with his cells in more than 1,000 mice and in guinea pigs before encountering the transient arrhythmias in monkeys — which came as a surprise.
“Our next steps are to get the arrhythmia problem sorted out,” Murry said. “We are working on improving the cells, advancing their maturity before transplantation. This should be doable, as we’ve made considerable progress already.”
Menasche agreed: “The truth is that it is the end of a long period of preclinical and translational work. But we are still learning a lot of things every day about these cells, and the way to optimize their use.”
Research like this illustrates exactly how long the path from preclinical discovery to human trials can be. Our introduction to clinical trials explains how Phase I safety studies like this cardiac progenitor cells trial fit into the broader clinical development pathway.
For those interested in parallel advances in regenerative medicine, our article on the spinal cord injuries stem cell trial covers another landmark first in human stem cell transplantation research.
According to the American Heart Association, heart failure affects approximately 6.2 million adults in the United States — making advances in cardiac progenitor cells research a critical priority for cardiovascular medicine.
Source: Bioscience Technology | October 30, 2014