S-Space College of Engineering/Engineering Practice School (공과대학/대학원) Dept. of Chemical and Biological Engineering (화학생물공학부) Theses (Ph.D. / Sc.D._화학생물공학부)
Nanoparticle-mediated Cell Behavior Modulation for the Treatment of Myocardial Infarction : 나노입자 기반, 세포 거동조절을 통한
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- 공과대학 화학생물공학부
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 공과대학 화학생물공학부, 2017. 8. 김병수.
- Myocardial infarction (MI) is one of the leading causes of death worldwide, and accounts for majority of cardiac-associated disorders. MI originates from reduced blood supply to the heart and subsequent cardiac necrosis, hence, tissue engineering approaches are required for successful cardiac repair. Recently, various types of cells and nanoparticles drew significant attention as efficient therapeutics for cardiac repair, and combinatorial treatments between cells and nanoparticles have been introduced. Even so, majority of nanomaterials have been mostly utilized as delivery carriers, and studies regarding how nanoparticles actively modulate cell behaviors and potentiate the therapeutic efficacy of these cells remain unexplored.
Current dissertation presents the integration of stem or immune cells with most widely used nanoparticles, such as iron oxide nanoparticles or graphene oxide, for the treatment of MI. More specifically, biological role of these nanoparticles and how innate chemical properties of nanoparticles mediate cell behaviors is elucidated. Major goals of dissertation are summarized as follows
1) Elucidation of metal ion-delivering capability of iron oxide nanoparticles, and investigation on the modulation of cell signaling transduction and development of intercellular gap junction crosstalk 2) Elucidation of sp2 chemistry-based intracellular antioxidant chemistry of graphene oxide, and its immune modulatory function for therapeutic polarization of macrophages in MI treatment.
First, we showed that iron oxide nanoparticles can modulate intracellular signaling transduction in cardiac cells, and improve intercellular gap junction formation in stem cell co-culture. Co-culture of stem cells with cardiac cells has windowed a platform for cardiac priming of MSCs prior to in vivo transplantation, and active gap junctional crosstalk between stem cells and cardiac cells are crucial in stem cell modification. In this study, we report that iron oxide nanoparticles can augment the expression of gap junction protein connexin 43 in cardiac cells to better form gap junction channels with stem cells. Stem cells co-cultured with nanoparticle-harboring cardiac cells exhibited active biomolecule transfer and showed increased level of electrophysiological cardiac biomarkers and cardiac repair-favorable paracrine secretion. Implanted in rat MI models, cardiac-primed stem cells significantly reduced cardiac fibrosis, promoted cardiac tissue regeneration and function.
Secondly, we exhibited that graphene oxide with carbon-based sp2 chemistry can function as reactive oxygen species scavenger within the cells and prevent inflammatory activation of macrophages. Furthermore, we functionalized graphene oxide nanoparticles with plasmid DNA to better polarize inflammatory cells at cardiac infarction area into tissue regenerative macrophages. After the onset of MI, excessive amount of inflammatory macrophages propagates at the peri-infarct to exacerbate tissue necrosis, suggesting that uncontrolled differentiation and activation of inflammatory macrophages greatly hamper proper tissue regeneration. In this study, we demonstrated that graphene oxides can act as an antioxidant to prevent inflammatory activation of macrophages, and further DNA functionalization significantly improved therapeutic polarization of these macrophages. Furthermore, injection of DNA-functionalized graphene oxides in mouse MI models notably reduced immune cell infiltration and mitigated cardiac fibrosis for cardiac performance improvement.
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