Harnessing Natural and Synthetic Materials as Therapeutic Approaches for Cardiac Repair

利用天然和合成材料作為心臟修復的治療方法

Student thesis: Doctoral Thesis

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Award date28 Nov 2023

Abstract

Myocardial infarction (MI), implications of occlusion in heart blood vessels, leads to ischemia and irreversible cardiomyocytes (CMs) death. Early reperfusion during MI, as a well-known approach for blood and oxygen restoration, however, will paradoxically induce new damage mainly due to the burst of oxygen, termed as ischemia/reperfusion(I/R) injury. Despite enormous efforts, there still lacks reliable therapy in clinics for treating MI or I/R injury, due to a low therapeutic efficacy or undesirable effects. This dissertation focuses on developing new strategies with solid curative outcomes for recusing myocardium and improving cardiac functions under MI or I/R injury. To achieve this goal, we exploited both natural materials (derived from mammalian cells or plants) and synthetic nanoparticles (NPs), as novel approaches to robustly fix the hearts, through seeking and harnessing their unique and unexplored advantages. In our first study, cardiac fibroblasts (CFs) were targeted for their heart extracellular matrix (ECM)-secreting capability. Through constructing an epicardial implantable cardiac patch using the ECM produced from human induced pluripotent stem cells(hiPSCs)-derived CFs, our study offers a clinical grade of cardiac biomaterial for autologous heart repair following MI, which was validated in vivo in a SD rat model demonstrating a minimal host response occurred during engraftment of SD rat-CF derived cardiac ECM patches. Secondly, as a response to diminish excessive reactive oxygen species (ROS) during I/R injury, in our following study, we extracted and identified a natural antioxidant from a maple tree leaf (Acer tataricum subsp. Ginnala) which exhibited excellent antioxidative capacity such catalase-like activity to responsively scavenge extracellular and intracellular ROS and protect the neonatal rat cardiomyocytes (NRCMs) and thus alleviate myocardium damage. In addition, those extracts were also found in preventing of ferroptosis and promoting cell energy state, uncovering their multiples roles in cardioprotection. Lastly, we doped platinum into cerium oxide (CeO2) NPs, a well-known antioxidative NPs, and synthesized CeO2-Pt NPs conferring enhanced efficiency of cellular internalization enabled heart healing without any toxicity, which was further evidenced from salvaged rat viable myocardium and improved heart function during I/R injury after in vivo administration. Of note, at the same dose, conventional CeO2 NPs did not exhibit any protective effects. In summary, this dissertation 1) devised a cardiac ECM-based autologous patch which allows the feasibility of dodging immune system thus enables an immunosuppressant-free condition for delivering therapeutic agents to injured hearts; 2) discovered the cardioprotective roles of maple tree leaf (Acer tataricum subsp. Ginnala) and 3) CeO2-Pt NPs against I/R injury by revealing their biological benefits, providing promising therapeutic approaches for cardiac repair.