Abstract
Despite improvements over the past 30 years, 10-year pediatric heart transplantation survival rates remain low and mechanical support is both expensive and relatively unavailable. In contrast to isolated cell therapies, implantable engineered cardiac tissues (ECTs) recover myocardial mass and function, creating the opportunity for cardiac recovery rather than replacement. Our ECT research has progressed from using embryonic avian and rodent cell compositions to human induced pluripotent stem cell (h-iPSC)-derived, multiple cell lineage formulations with the goal of clinical translation. We generate ECTs from h-iPSC-derived cardiomyocytes (CM), endothelial cells (EC), and vascular mural cells (MC) in both linear (15 × 1 mm) and large format (LF, 20 × 20 mm) geometries using rodent-derived and human-compatible reagents. H-iPSC ECTs undergo rapid gel compaction and begin intrinsic beating by day 3. CM fraction at ECT formation is approximately 60%. The ECT maximum capture rates increased during in vitro culture up to 28 days and in response to optogenetic pacing (OP) using AAV-ChIEF from day 7 to 14. ECT relaxation times decreased, force-frequency relations became more neutral, and beat-to-beat hysteresis decreased with prolonged culture or OP. H-iPSC-derived ECTs generated using human collagen I and human compatible MaxGel have comparable structural and functional features to rodent-derived ECTs. Linear and LF-ECTs implanted onto xenotolerant infarcted rat hearts survived, engrafted, improved ejection fraction, normalized regional echo strain, and reduced scar area at 4 weeks. Thus, these h-iPSC ECT compositions show promise as a strategy for pediatric myocardial recovery.
Highlights
Despite dramatic progress in the surgical management and survival of infants with complex congenital heart defects, myocardial injury following cardiac surgery and progressive cardiac dysfunction results in significant morbidity and mortality
We developed and validated methods to generate linear (15 mm length × 1 mm diameter) engineered cardiac tissues (ECTs) from human iPSCs-derived CV lineages (h-iPSC- ECTs) [11]
We found that the coexistence of endothelial cells (EC) and mural cells (MC) vascular lineages with CMs within the 3D ECT compositions promoted tissue maturation (Fig. 54.1)
Summary
Despite dramatic progress in the surgical management and survival of infants with complex congenital heart defects, myocardial injury following cardiac surgery and progressive cardiac dysfunction results in significant morbidity and mortality. While cells from multiple vertebrate species have been used to investigate ECT structural and functional maturation and to model cardiomyopathies, it is clear that human cells are required for clinical trials and future therapies. Multiple studies have validated the ability of h-iPSC-derived CM to mature and form implantable cell sheets [21]. To advance this paradigm, we developed and validated methods to generate linear (15 mm length × 1 mm diameter) ECTs from human iPSCs-derived CV lineages (h-iPSC- ECTs) [11]. We demonstrated the therapeutic potential of h-iPSC ECTs in an immune-tolerant rat myocardial infarction (MI) model showing the improvement of cardiac function with regenerated myocardium and enhanced angiogenesis [11]
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