The significance of this research
A research team led by Professor Steven Goldman at the Sarver Heart Center of the University of Arizona, developed a patch for the treatment of chronic heart failure (CHF), which was embedded with human neonatal fibroblasts and human induced pluripotent stem cell (hiPSC)–derived cardiomyocytes (hiPSC-CMs). The patch was implanted in a rat model of heart failure, and they confirmed the efficacy of the treatment. Since this patch is robust, easy to handle, and bioabsorbable, its clinical application is expected.
Current treatment for heart failure
The heart pumps blood throughout the body by regularly repeating contractions and dilations. Heart failure causes symptoms such as shortness of breath and swelling because the pumping function is impaired. Heart failure is mainly treated by medication. However, as the condition worsens, medication becomes less and less effective. Therefore, the only way to treat late-stage heart failure is to use a left ventricular assist device (LVAD), an artificial heart pump, or wait for a heart transplant.
Transplantation of hiPSC-CMs
The heart consists mostly of cardiac muscle cells, or myocardium. It is expected that transplantation of hiPSC-CMs will improve heart function in patients with heart failure. However, clinical testing of cell therapy has been shown to be safe but with limited efficacy. Injected cells cannot survive transplantation, so other transplantation approaches are needed.
Results of this study
First, the research team developed a patch composed of a robust and bioabsorbable knitted mesh embedded with human neonatal fibroblasts and cocultured with hiPSC-CMs. The fibroblasts secrete angiogenic growth factors that increase myocardial blood flow and provide a mechanical scaffold for cardiomyocytes.
The heart’s electrical system controls the timing of heart contraction by sending electrical signals through cardiomyocytes. Contractions were observed on a cellular and patch level. The patches beat spontaneously and synchronously with no electrical input at 36 ± 5 beats/min. When electrical stimulation was applied, all patches contracted in response to the stimulation.
Next, they created CHF model in rats by left coronary artery ligation, which cuts off the blood flow to cardiomyocytes and induces an artificial myocardial infarction. Coronary arteries are blood vessels that carry oxygen and nutrients to cardiomyocytes. Cardiomyocytes around the infarct coronary artery dies, which causes CHF. Three weeks after left coronary ligation, a hiPSC-CM patch was implanted over the infarcted region.
Echocardiography was performed 3 weeks after the implantation. In CHF model, diastolic dysfunction occurred and the wall thickness in the infarcted region was reduced. In contrast to this, the wall thickness was increased, and diastolic dysfunction was improved in the patch-treated CHF rats.
Electric signals are not transmitted across the infarcted myocardium, which causes lethal arrhythmias. In the patch-treated CHF rats, there was propagation of the electrical signals across the patch in congruity with the underlying myocardium. There were no arrhythmias after implantation of the patch.
These results confirmed that implantation of a fibroblasts/hiPSC-CMs patch electrically enhanced conduction, and improved diastolic function in rats with CHF.
Additional information for researchers
At 21 days after implantation, the patch increased myocyte density in the previously infarcted region. On the other hand, transplanted hiPSC-CMs were present at 7 days but not detected at 21 days. Rats with the patch showed significant increases in expression of connection 43 (Cx43), angiopoetin 1 (ANG1), vascular endothelial growth factor (VEGF), β-myosin heavy chain 7 (βMYH7), and insulin growth factor 1 (IGF-1) compared with CHF rats. These cytokine expressions may help preserve or regenerate myocardium.
Article: “Human Induced Pluripotent Stem Cell–Derived Cardiomyocyte Patch in Rats With Heart Failure”
Authors: Jordan J. Lancaster, PhD, Pablo Sanchez, MD, Giuliana G. Repetti, BA, Elizabeth Juneman, MD, Amitabh C. Pandey, MD, Ikeotunye R. Chinyere, BS, Talal Moukabary, MD, Nicole LaHood, MD, Sherry L. Daugherty, BS, and Steven Goldman, MD