Abstract
Human induced pluripotent stem cells (hiPSCs) are a robust source for cardiac regenerative therapy due to their potential to support autologous and allogeneic transplant paradigms. The in vitro generation of three-dimensional myocardial tissue constructs using biomaterials as an implantable hiPSC-derived myocardium provides a path to realize sustainable myocardial regeneration. We generated engineered cardiac tissues (ECTs) from three cellular compositions of cardiomyocytes (CMs), endothelial cells (ECs), and vascular mural cells (MCs) differentiated from hiPSCs. We then determined the impact of cell composition on ECT structural and functional properties. In vitro force measurement showed that CM+EC+MC ECTs possessed preferential electromechanical properties versus ECTs without vascular cells indicating that incorporation of vascular cells augmented tissue maturation and function. The inclusion of MCs facilitated more mature CM sarcomeric structure, preferential alignment, and activated multiple tissue maturation pathways. The CM+EC+MC ECTs implanted onto infarcted, immune tolerant rat hearts engrafted, displayed both host and graft-derived vasculature, and ameliorated myocardial dysfunction. Thus, a composition of CMs and multiple vascular lineages derived from hiPSCs and incorporated into ECTs promotes functional maturation and demonstrates myocardial replacement and perfusion relevant for clinical translation.
Highlights
Among the stem cell types, pluripotent stem cells [Embryonic stem cells (ESCs)/induced pluripotent stem cells] possess great potential for cardiac regeneration due to their capacity for robust in vitro expansion followed by directed differentiation into most somatic cell lineages including CMs or other vascular cell types[11,12]
We optimized our previously reported human iPSC (hiPSC) cardiovascular cell induction protocol to induce CMs along with endothelial cells (ECs)[8] which resulted in the efficient induction of cardiac troponin-T+ CMs (61.8 ± 8.0% of total cells) and vascular endothelial (VE)-cadherin (CD144)+ ECs (19.4 ± 9.1%) with little co-induction of platelet-derived growth factor receptor beta (PDGFRβ;CD140b)+ vascular mural cells (MCs) (1.7 ± 2.0%) by day 15 (d15; n = 26) (Supplementary Fig. 1; compared to those without MCs (CM+EC) protocol)
We successfully generated a novel 3D engineered cardiac tissues (ECTs) composition of hiPSC-derived cardiomyocytes, vascular endothelial cells, and mural cells that displays excellent in vitro structural maturation and electromechanical performance, is capable of in vivo survival, remodeling, and perfusion post-implantation, and contributes to myocardial repair and recovery
Summary
Among the stem cell types, pluripotent stem cells [Embryonic stem cells (ESCs)/induced pluripotent stem cells (iPSCs)] possess great potential for cardiac regeneration due to their capacity for robust in vitro expansion followed by directed differentiation into most somatic cell lineages including CMs or other vascular cell types[11,12]. We have reported that co-existence of CMs and vascular cell lineages within mouse ESC-engineered cell sheet structure augmented cell sheet function[10], and the transplantation of cell sheets engineered from human iPSC (hiPSC)-derived multiple cardiac lineages (cardiac tissue sheets) brought functional recovery and myocardial regeneration on a rat myocardial infarction (MI) model[8]. We hypothesized that ECTs composed by human iPSC (hiPSC)-derived cardiovascular cells hold promise to realize an ideal 3D structure for clinical application. We utilize a strategy that identified an optimal composition of multiple cardiovascular cell populations derived from hiPSCs to generate ECT grafts with improved tissue maturation and with excellent post-implantation survival, perfusion, and contribution to functional recovery relevant to clinical application
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