Researchers at the University of Wisconsin-Madison and the Mayo Clinic have demonstrated that heart muscle cells grown from human stem cells can safely integrate into the hearts of monkeys with right ventricular pressure overload, a condition that often affects children born with congenital heart defects.
Stem Cell Grafts Target Right Ventricular Dysfunction
Heart disease, the No. 1 killer of Americans, can affect people at any time across their lifespans—even starting from birth. When heart conditions are present at birth, they are classified as congenital heart defects. Among these, nearly all single ventricle congenital heart defects, particularly those in the right ventricle, eventually lead to heart failure.
Traditional surgical interventions for these structural issues often serve merely as temporary fixes. Eventually, many patients require a heart transplant. However, finding viable donor hearts is extremely limited, a challenge made even steeper by the young age at which most affected patients need the procedure. To address this shortage, investigators are exploring whether regenerating tissue to support healthy heart function can keep compromised hearts functioning longer.
In a recent publication, a collaborative research team examined whether grafts of stem cell-derived cardiomyocytes could serve as a complementary therapy alongside conventional surgical repair. The primary objective was to directly support ventricular function and overall healing. Stem cell treatments could someday delay or even prevent the need for heart transplants.
Preclinical Safety and Cellular Integration in Nonhuman Primates
To evaluate the feasibility and safety of this approach, the research team utilized rhesus macaque monkeys with surgically induced right ventricular pressure overload. Scientists collected clinical-grade human induced pluripotent stem cells—derived from human donors, returned to a stem cell state, and subsequently developed into cell types compatible with heart muscle—and transplanted them directly into the animal models.
Monitoring throughout the evaluation period revealed that the transplanted material successfully integrated into the organization of the host myocardium. Yet, the procedure was not without temporary complications. The authors observed that episodes of ventricular tachycardia occurred in five out of 16 animals that received the cell grafts, with two subjects exhibiting incessant tachycardia. Fortunately, these elevated heart rate episodes resolved within 19 days.
“We delivered the cells to support existing cardiac tissue, Our goal with this particular study, as a precursor to human studies, was to make sure that the transplanted cells were safe and would successfully integrate with the organization of the surrounding tissue. We leveraged my team’s experience with stem cells and cardiac evaluation in Parkinson’s disease to assess this innovative therapeutic approach.”
Marina Emborg, professor of medical physics in the UW-Madison School of Medicine and Public Health
Understanding Cardiac Development and Tissue Complexity
The successful integration of these cells builds on foundational knowledge regarding how the heart forms and functions during embryogenesis. The heart is one of the first organs to form and function. It relies on multiple cell lineages—including cardiomyocytes, endothelial cells, epicardial cells, and neural crest cells—which coordinate through paracrine interactions, cell-ECM interactions, and cell-cell interactions to facilitate survival, growth, proliferation, differentiation and migration of cardiac tissue.
Proper mammalian heart anatomy depends on a multi-chambered structure divided into the left atrium, left ventricle, right atrium, and right ventricle. Deoxygenated blood returning from the body through the inferior and superior vena cava enters the heart through the right atrium, moves through the tricuspid valve into the right ventricle, and is then pumped toward the lungs via the pulmonary arteries for oxygenation. Pulmonary veins subsequently return oxygenated blood to the left atrium, which contracts through the mitral valve to fill the left ventricle—the main pumping chamber—before the blood is ejected through the aorta and into the major circulatory network of the body.
Aberrant regulation of any of these processes can induce developmental disorders and pathological phenotypes. Investigating how cardiac cells proliferate, differentiate, and migrate remains vital to understanding the causes of congenital heart defects and discovering new therapeutics for pediatric and adult cardiac disease in the near future.
Path Toward Clinical Application
Macaques, in particular, have been critical to advancing stem cell therapies for heart disease, kidney disease, Parkinson’s disease, eye diseases and more. Establishing the feasibility and safety in the first nonhuman primate model of right ventricular pressure overload marks a notable milestone for regenerative medicine.
The demonstration of successful integration and maturation of the cells into a compromised heart is a promising step towards the clinical application for congenital heart defects,
Emborg noted in findings detailed by the research announcement. Funding for the work was provided by the Todd and Karen Wanek Family Program for Hypoplastic Left Heart Syndrome alongside National Institutes of Health Grant P51OD011106 to the Wisconsin National Primate Research Center.
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