Abstract
Background Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are under preclinical investigation as a cell-based therapy for heart failure post-myocardial infarction. In a previous study, tissue-engineered cardiac grafts were found to improve hosts' cardiac electrical and mechanical functions. However, the durability of effect, immune response, and in vitro properties of the tissue graft remained uncharacterized. This present study is aimed at confirming the graft therapeutic efficacy in an immune-competent chronic heart failure (CHF) model and providing evaluation of the in vitro properties of the tissue graft. Methods hiPSC-CMs and human dermal fibroblasts were cultured into a synthetic bioabsorbable scaffold. The engineered grafts underwent epicardial implantation in infarcted immune-competent male Sprague-Dawley rats. Plasma samples were collected throughout the study to quantify antibody titers. At the study endpoint, all cohorts underwent echocardiographic, hemodynamic, electrophysiologic, and histopathologic assessments. Results The epicardially placed tissue graft therapy improved (p < 0.05) in vivo and ex vivo cardiac function compared to the untreated CHF cohort. Total IgM and IgG increased for both the untreated and graft-treated CHF cohorts. An immune response to the grafts was detected after seven days in graft-treated CHF rats only. In vitro, engineered grafts exhibited responsiveness to beta-adrenergic receptor agonism/antagonism and SERCA inhibition and elicited complex molecular profiles. Conclusions This hiPSC-CM-derived cardiac graft improved systolic and diastolic cardiac function in immune-competent CHF rats. The improvements were detectable at seven weeks post-graft implantation despite an antibody response beginning at week one and peaking at week three. This suggests that non-integrating cell-based therapy delivered by a bioengineered tissue graft for ischemic cardiomyopathy is a viable treatment option.
Highlights
Heart failure (HF) with reduced ejection fraction carries a mortality of over 30% within five years of the initial hospitalization [1, 2]
A previous study from our laboratory demonstrated that tissue-engineered (TE) cardiac grafts composed of human neonatal dermal fibroblasts seeded on bioabsorbable scaffolds induced angiogenesis and increased myocardial blood flow in rodents with HF after myocardial infarction (MI) [5]
A more recent study showed that hiPSCCMs seeded on the same fibroblast scaffold improved cardiac function in the same rodent model of HF [6] Interestingly, Stem Cells International these benefits were observed using a xenograft transplant of human fibroblasts and human induced pluripotent stem cells (hiPSCs)-CMs in immune-competent Sprague-Dawley rats, in which we have shown that the transplanted cells do not persist [6]
Summary
Heart failure (HF) with reduced ejection fraction carries a mortality of over 30% within five years of the initial hospitalization [1, 2]. A more recent study showed that hiPSCCMs seeded on the same fibroblast scaffold improved cardiac function in the same rodent model of HF [6] Interestingly, Stem Cells International these benefits were observed using a xenograft transplant of human fibroblasts and hiPSC-CMs in immune-competent Sprague-Dawley rats, in which we have shown that the transplanted cells do not persist [6]. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are under preclinical investigation as a cell-based therapy for heart failure post-myocardial infarction. This hiPSC-CM-derived cardiac graft improved systolic and diastolic cardiac function in immune-competent CHF rats. The improvements were detectable at seven weeks post-graft implantation despite an antibody response beginning at week one and peaking at week three This suggests that non-integrating cell-based therapy delivered by a bioengineered tissue graft for ischemic cardiomyopathy is a viable treatment option
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