Japanese researchers are testing cardiac spheroids for heart regeneration in monkeys

Japanese researchers are testing cardiac spheroids for heart regeneration in monkeys

Regenerative heart therapies involve transplanting heart muscle cells into damaged areas of the heart to restore lost functions. However, the risk of cardiac arrhythmias following this procedure is reportedly high. In a recent study, researchers from Japan tested a novel approach in which “cardiac spheroids” cultured from human stem cells are injected directly into damaged ventricles. The extremely positive results observed in primate models highlight the potential of this strategy.

Cardiovascular diseases are still one of the most common causes of death worldwide and are particularly common in industrialized countries. Myocardial infarctions, commonly known as “heart attacks,” are increasing and result in a significant number of deaths each year.

Heart attacks typically kill millions of heart muscle cells, weakening the heart. Because mammals cannot regenerate cardiac muscle cells themselves, heart transplants are currently the only clinically viable option for patients suffering from (or likely to suffer from) heart failure. Given that complete heart transplants are expensive and obtaining donors is difficult, it is not surprising that alternative therapies are in high demand in the medical community.

A promising strategy that is becoming increasingly important is the use of human induced pluripotent stem cells (HiPSCs) for regenerative cardiac therapy. Simply put, HiPSCs are cells that come from mature cells and can be effectively “reprogrammed” into a completely different cell type, such as heart muscle cells (cardiomyocytes). By transplanting or injecting cardiomyocytes derived from HiPSCs into damaged areas of the heart, it is possible to restore some of the lost functionality. Unfortunately, studies have shown that this approach can increase the risk of cardiac arrhythmias, which represents a major hurdle for 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 heart therapy by injecting monkeys with myocardial infarction with “cardiac spheroids” made from HiPSCs. This study was published in the journal on April 26, 2024Trafficwas led by Professor Yuji Shiba from the Department of Regenerative Science and Medicine 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.

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 collections of cardiac cells) from the cultures, they injected approximately 6 × 107 cells into the damaged hearts of crab-eating macaques (Macaca fascicularis). They monitored the animals' condition for twelve weeks and regularly measured their heart function. They then analyzed the monkeys' hearts at the tissue level to determine whether cardiac spheroids could regenerate the damaged heart muscles.

First, the team checked the correct reprogramming of HiPSCs into cardiomyocytes. Using electrical measurements at the cellular level, they observed that the cultured cells exhibited potential patterns typical of ventricular cells. The cells also responded as expected to various known medications. Most importantly, they found that the cells expressed abundant 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, 230 km away. The cardiac spheroids, preserved at 4 °C in standard containers, survived the four-hour journey without any problems. This means that no extreme cryogenic measures would be required when transporting the cells to clinics, making the proposed approach more cost-effective and easier to implement.

Finally, the monkeys received injections of either cardiac spheroids or a placebo directly into the damaged heart chamber. During the observation period, researchers found that arrhythmias occurred very rarely and only two people in the treatment group experienced transient tachycardia (rapid pulse) in the first two weeks. Using echocardiography and computed tomography scans, the team confirmed that after four weeks, the hearts of the treated monkeys had better left ventricular output compared to the control group, indicating better blood pumping ability.

Histological analysis ultimately revealed that the heart grafts were mature and properly attached to pre-existing tissue, supporting the results of previous observations. “HiPSC-derived cardiac spheroids could potentially serve as an optimal form of cardiomyocyte products for cardiac regeneration due to their straightforward generation process and effectiveness," notes Assistant Professor Kobayashi. "We believe that the results of this research will help solve the main problem of ventricular arrhythmia occurring after cell transplantation and significantly accelerate the realization of cardiac regenerative therapy.“ he further adds.

Although it was tested in monkeys, it is worth noting that the cardiac spheroid preparation protocol used in this study was designed for clinical use in humans. “The positive results achieved so far are sufficient to give the green light for our clinical study, the so-called LAPiS study. We are already using the same cardiac spheroids in patients with ischemic cardiomyopathy,“ comments Asst. Prof. Kobayashi.

Let us all hope for a resounding success of the LAPiS study, paving the way for expanded and effective treatment options for people with heart problems.

Sources: