Abstract
The current study describes a scalable, porous large-format engineered cardiac tissue (LF-ECT) composed of human induced pluripotent stem cells (hiPSCs) derived multiple lineage cardiac cells with varied 3D geometries and cell densities developed towards the goal of scale-up for large animal pre-clinical studies. We explored multiple 15 × 15 mm ECT geometries using molds with rectangular internal staggered posts (mesh, ME), without posts (plain sheet, PS), or long parallel posts (multiple linear bundles, ML) and a gel matrix containing hiPSC-derived cardiomyocytes, endothelial, and vascular mural cells matured in vitro for 14 days. ME-ECTs displayed the lowest dead cell ratio (p < 0.001) and matured into 0.5 mm diameter myofiber bundles with greater 3D cell alignment and higher active stress than PS-ECTs. Increased initial ECT cell number beyond 6 M per construct resulted in reduced cell survival and lower active stress. The 6M-ME-ECTs implanted onto 1 week post-infarct immune tolerant rat hearts engrafted, displayed evidence for host vascular coupling, and recovered myocardial structure and function with reduced scar area. We generated a larger (30 × 30 mm) ME-ECT to confirm scalability. Thus, large-format ECTs generated from hiPSC-derived cardiac cells may be feasible for large animal preclinical cardiac regeneration paradigms.
Highlights
Tissue engineering technologies have emerged as robust modalities to realise cardiac regeneration due to the unique capacity to deliver numerous cardiac cells within an organised architecture onto the heart[13,14,15,16,17]
We demonstrated the therapeutic potential of human induced pluripotent stem cells (hiPSCs)-engineered cardiac tissues (ECTs) in an immune tolerant rat myocardial infarction (MI) model showing the improvement of cardiac function with regenerated myocardium and enhanced angiogenesis
Once we determined the structural and functional advantage of the ME-ECT geometry, we explored the impact of altered initial cell seeding number and seeding density on cell viability and in vitro large-format hiPSC-ECT (LF-ECT) structural and functional maturation
Summary
Tissue engineering technologies have emerged as robust modalities to realise cardiac regeneration due to the unique capacity to deliver numerous cardiac cells within an organised architecture onto the heart[13,14,15,16,17]. We reported the generation of three-dimensional (3D) linear engineered cardiac tissues (ECTs) from chick embryonic or rat fetal cardiomyocytes (CMs) and biomaterials as a robust in vitro model to elucidate the development of embryonic myocardium and a platform to realise cardiac regeneration via implantation therapy for injured myocardium[18,19]. In order to advance this technology towards clinical application, we developed and validated a method to generate linear ECTs from human iPSCs-derived CV lineages (hiPSC-ECTs)[8]. We have expanded our hiPSC-ECT technology to develop a novel large-format hiPSC-ECT (LF-ECT) through optimisation of geometry and cellular composition in order to promote in vitro pre-implant cell survival and satisfactory engraftment after in vivo implantation onto animal hearts
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