Regenerative cardiac therapies involve transplanting heart muscle cells into damaged areas of the heart to restore lost function. However, the risk of arrhythmias after this procedure is reported to be high. In a recent study, researchers in Japan tested a novel approach of injecting ‘cardiac spheroids’, grown from human stem cells, directly into damaged ventricles. The highly positive results observed in primate models highlight the potential of this strategy.
Cardiovascular diseases remain among the leading causes of death worldwide and are especially prevalent in developed countries. Myocardial infarctions, commonly known as “heart attacks”, are increasing and cause a significant number of deaths each year.
Heart attacks typically kill millions of heart muscle cells, leaving the heart weakened. Since mammals cannot regenerate heart muscle cells on their own, heart transplants are currently the only clinically viable option for patients suffering from (or likely to suffer from) heart failure. Since whole heart transplants are expensive and donors are difficult to obtain, it is not surprising that the medical community is looking for alternative therapies.
One promising strategy that has been steadily gaining ground is the use of human induced pluripotent stem cells (HiPSCs) for regenerative cardiac therapy. Simply put, HiPSCs are cells derived from mature cells that can be effectively “reprogrammed” into a completely different cell type, such as cardiac muscle cells (cardiomyocytes). By transplanting or injecting HiPSC-derived cardiomyocytes into damaged areas of the heart, it is possible to recover some of the lost functionality. Unfortunately, studies have reported that this approach may increase the risk of arrhythmias, posing a major obstacle to clinical trials.
In a recent study, a Japanese research team from Shinshu University and Keio University School of Medicine tested a new strategy for regenerative cardiac therapy that involves injecting HiPSC-derived “cardiac spheroids” into monkeys with myocardial infarction. This study, published on April 26, 2024, in the journal Circulationwas led by Professor Yuji Shiba of the Department of Medicine and Regenerative Sciences at Shinshu University.
The team included Hideki Kobayashi, the first author, and Koichiro Kuwahara from the Department of Cardiovascular Medicine at Shinshu University School of Medicine, as well as Shugo Tohyama and Keiichi Fukuda from the Department of Cardiology at Keio University School of Medicine. , among others.
In their novel approach, the researchers cultured HiPSCs in a medium that led to their differentiation into cardiomyocytes. After carefully extracting and purifying cardiac spheroids (three-dimensional clumps of cardiac cells) from the cultures, they injected approximately 6 × 107 cells in the damaged hearts of cynomolgus macaques (fascicular macaca). They monitored the animals’ condition for twelve weeks, taking periodic measurements of heart function. They next analyzed the monkeys’ hearts at the tissue level to assess whether the cardiac spheroids could regenerate damaged heart muscles.
First, the team verified the correct reprogramming of HiPSCs into cardiomyocytes. They observed, through electrical measurements at the cellular level, that the cultured cells presented potential patterns typical of ventricular cells. The cells also responded as expected to several known drugs. Most importantly, they discovered that the cells abundantly expressed adhesive proteins such as connexin 43 and N-cadherin, which would promote their vascular integration into an existing heart.
The cells were then transported from the Keio University production facility to Shinshu University, located 230 kilometers away. The cardiac spheroids, which were stored at 4°C in standard containers, withstood the four-hour trip without problems. This means that extreme cryogenic measures would not be needed when transporting the cells to clinics, making the proposed approach less expensive and easier to adopt.
Finally, the monkeys received injections of cardiac spheroids or a placebo directly into the damaged cardiac ventricle. During the observation period, researchers noted that arrhythmias were very rare, and only two people experienced transient tachycardia (rapid pulse) in the first two weeks among the treatment group. Using echocardiography and CT scans, the team confirmed that the hearts of the treated monkeys had better left ventricular ejection after four weeks compared to the control group, indicating a superior blood-pumping capacity.
Histological analysis finally revealed that the cardiac grafts were mature and adequately connected to the preexisting tissue, consolidating the results of previous observations. “HiPSC-derived cardiac spheroids could serve as an optimal form of cardiomyocyte products for heart regeneration, given their simple generation process and efficacy.“comments Assistant Professor Kobayashi. “We believe that the results of this research will help solve the major problem of ventricular arrhythmia occurring after cell transplantation and greatly accelerate the realization of cardiac regenerative therapy.“he further adds.
Although tested in monkeys, it is worth noting that the cardiac spheroid production protocol used in this study was designed for clinical application in humans. “The favorable results obtained so far are sufficient to give the green light to our clinical trial, called LAPiS trial. We are already using the same cardiac spheroids in patients with ischemic cardiomyopathy,“comments assistant professor Kobayashi.
Let us all hope for a resounding success in the LAPiS trial, paving the way for expanded and effective treatment pathways for people suffering from heart problems.