In a groundbreaking study in cardiac research, scientists have shown that recovery from heart attacks could potentially be improved by injecting spheroids made of heart muscle cells derived from human induced pluripotent stem cells (hiPSCs).
This innovative approach involves the use of specially designed cell spheroids that overexpress cyclin D2 while lacking human leukocyte antigen classes I and II.
The research, published in the journal *Circulation Research*, was conducted using a porcine model—an approach considered more applicable to human heart physiology than traditional mouse studies due to anatomical similarities.
Innovative Approach to Cardiac Recovery
The project was spearheaded by Jianyi “Jay” Zhang, M.D., Ph.D., and Lei Ye, M.D., Ph.D., at the University of Alabama at Birmingham (UAB).
The researchers engineered hiPSCs that are knockout for human leukocyte antigens and simultaneously overexpress cyclin D2, resulting in what they termed KO/OEhiPSCs.
After these cells underwent differentiation, the researchers converted them into cardiomyocyte spheroids, which were then implanted into pig hearts that had incurred ischemia and reperfusion injuries.
The results were striking; this method not only enhanced cardiac function but also led to a notable reduction in the size of the infarct four weeks later.
Effects on Heart Function and Cell Proliferation
Previous research has illustrated a clear link between the extent of heart muscle damage (infarct size) and subsequent remodeling of the left ventricle, a process that can result in heart failure.
In this study, the team observed a stark 35.8 percent decrease in infarct size among pigs treated with KO/OEhiPSC-derived cardiomyocyte spheroids compared to those receiving standard treatment or wild-type hiPSC-derived spheroids.
What is particularly intriguing is that, rather than the injected cells remaining and integrating within the damaged heart tissue, the proliferation of the pigs’ own cardiomyocytes appeared to be primarily responsible for the observed improvements in cardiac health.
In mammals, heart muscle cells typically lose their ability to replicate shortly after birth, which complicates repair processes following a heart attack.
Past strategies aimed at enhancing heart repair by injecting new muscle cells often face challenges related to cell engraftment and growth.
Four weeks after implantation, the KO/OEhiPSC-derived spheroids showed limited persistence, yet the treated pig hearts exhibited a significant increase in the proliferation of their existing cardiomyocytes.
These cells not only showed heightened levels of various proliferation markers but also displayed elevated gene expression linked to DNA replication.
Furthermore, the study identified upregulation in three critical signaling pathways: Mitogen-Activated Protein Kinase, HIPPO/YAP, and Transforming Growth Factor β.
Potential for Future Therapies
As the researchers delved deeper into the heart cells, they analyzed the expression of receptors associated with these pathways and evaluated levels of extracellular proteins that interact with these receptors.
Interestingly, they found no significant differences in the expression of these proteins within the endogenous cardiomyocytes, suggesting that the proliferation of these muscle cells might be influenced by extracellular factors released by the injected KO/OEhiPSC-cardiomyocytes.
Among the cytokines assessed, follistatin emerged as a promising candidate for stimulating heart muscle cell division.
High levels of this autocrine glycoprotein were secreted by the modified cardiomyocytes.
In controlled experiments, human cardiomyocytes treated with follistatin exhibited a 30 percent increase in proliferation, surpassing control groups.
Additionally, earlier preclinical studies in mice confirmed that injected follistatin contributed to the proliferation of adult mouse cardiomyocytes after heart attacks.
Subsequent tests reinforced follistatin’s role in activating the HIPPO/YAP signaling pathway to promote cardiomyocyte growth.
This study pioneers the exploration of follistatin’s effects on facilitating the growth of both hiPSC-derived cardiomyocytes and the body’s own heart muscle cells in mature mammals.
While the exact mechanisms by which follistatin encourages this proliferation are yet to be fully understood, these findings open promising avenues for new therapies aimed at tackling the critical issue of heart attacks.
Given that heart failure accounts for around 13 percent of deaths worldwide, and many patients face a grim prognosis, the urgency for innovative solutions for heart attack survivors cannot be overstated.
Heart attacks lead to the death of cardiomyocytes due to blocked coronary arteries, resulting in fibrous scar tissue that hampers heart function and heightens the risk of serious complications.
This research builds upon previous work by Zhang and his colleagues, which suggested that heart muscle cells overexpressing cyclin D2 could support recovery from heart attacks, although those earlier studies were conducted in immunocompromised mice.
The current investigation advances this therapeutic strategy by creating hypoimmunogenic and cyclin D2-overexpressing hiPSC-derived cardiomyocytes, paving the way for possible clinical applications that could significantly improve outcomes for heart attack patients.
Zhang highlighted the potential of KO/OEhiPSC-derived cardiomyocytes to stimulate the growth of the heart’s own muscle cells in adult patients, leading to an exciting path forward in cardiac recovery.
Source: ScienceDaily