Development of a biomimetic mechanical stimulation system to improve the maturation of human ips-derived myocardial grafts

Resumo

Cardiac tissue engineering has transitioned from cardiac tissues derived from various animal species to the production of the first generation of human engineered cardiac tissues. Particularly, induced pluripotent stem cells (iPSC) provide a potential solution to current diseases of heart failure by providing a suitable source of autologous human cardiomyocytes (CMs) to support heart regeneration. Stem cell-derived CMs are often electro- and mechano-physiologically immature, which represents a critical barrier to their in-vitro and in-vivo application. Therefore, the purpose of this study was to fabricate human iPSC-derived CM grafts and study whether mechanical stimulation could enhance the maturation of the engineered constructs, and evaluate their in-vivo regeneration potential after myocardial infarction (MI) in a mouse model. With that purpose, keratinocyte iPS cells were derived to CM, mixed with collagen and other matrix factors to fabricate the constructs, and mechanically stimulated in a novel pumping system designed to apply a biomimetic mechanical pumping to the scaffolds. Maturation was studied by immunofluorescence, electron microscopy, and quantitative real-time polymerase chain reaction. In-vivo, the constructs were implanted onto the peri-infarct region of hearts after coronary artery ligation, and functionally and histologically analyzed 4 weeks post-implantation. Animals treated with our scaffolds experimented an enhanced recovery cardiac functions in comparison with non-treated controls.