Cardiac repair in guinea pigs with human engineered heart tissue from induced pluripotent stem cells

Abstract

Myocardial injury results in a loss of contractile tissue mass that, in the absence of efficient regeneration, is essentially irreversible. Transplantation of human pluripotent stem cell-derived cardiomyocytes has beneficial but variable effects. We created human engineered heart tissue (hEHT) strips from human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and hiPSC-derived endothelial cells. The hEHTs were transplanted onto large defects (22% of the left ventricular wall, 35% decline in left ventricular function) of guinea pig hearts 7 days after cryoinjury, and the results were compared with those obtained with human endothelial cell patches (hEETs) or cell-free patches. Twenty-eight days after transplantation, the hearts repaired with hEHT strips exhibited, within the scar, human heart muscle grafts, which had remuscularized 12% of the infarct area. These grafts showed cardiomyocyte proliferation, vascularization, and evidence for electrical coupling to the intact heart tissue in a subset of engrafted hearts. hEHT strips improved left ventricular function by 31% compared to that before implantation, whereas the hEET or cell-free patches had no effect. Together, our study demonstrates that three-dimensional human heart muscle constructs can repair the injured heart.

Therapeutic approaches for cardiac regeneration and repair

“…Furthermore, tissue-engineering technologies have allowed the building of myocardial patches and sheets and 3D heart tissues recapitulating in vitro the complex structure of heart tissue. Engineered heart tissues can be directly transplanted to the damaged heart and have been shown to improve therapeutic outcomes 198–201 . Meanwhile, the number of deliveries of the therapeutic factor might also be important, because repetitive delivery of stem cells was shown to improve therapeutic outcomes compared with a single delivery 202 .…”

Defined Engineered Human Myocardium With Advanced Maturation for Applications in Heart Failure Modeling and Repair

“…Early tissue engineering studies in chick embryo and rodent models have established electromechanical stimulation as an important engineering paradigm 8–10 , which has now been translated to human models 11–16 . The accumulating evidence for advanced maturation in three-dimensional versus monolayer cultures provides a solid rationale for applications in phenotypic screens 11 and heart repair 17, 18 . As the use of myocardial tissue engineering increases in academia and industry it is essential to establish conditions readily adaptable to current good manufacturing practice (cGMP).…”

Impact of Cell Composition and Geometry on Human Induced Pluripotent Stem Cells-Derived Engineered Cardiac Tissue

“…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 heart1314151617. Previously, 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 myocardium1819.…”