Author ORCID Identifier
Document Type
Thesis
Date of Award
2026
Degree Name
Master of Science (MS)
Department
Health Science
First Advisor
William WC Chen
Abstract
Despite significant advances in reperfusion and pharmacological therapies, effective strategies to modulate the post-infarction inflammatory response remain limited, leaving a critical gap in improving cardiac repair and long-term outcomes. Excessive or prolonged inflammation after myocardial infarction (MI) drives cardiac remodeling and fibrosis, impairing myocardial recovery and increasing the risk of heart failure (HF) or recurrent ischemic events. I hypothesize that appropriate immunomodulation after MI may reduce unwanted inflammation and improve heart function. Interleukin‑10 (IL‑10) is a pleiotropic immunomodulatory cytokine with therapeutic promise for limiting excessive inflammation and improving tissue repair in ischemic hearts. However, two translational barriers remain for applying IL-10 in cardiac immunomodulation: 1) the effective therapeutic window is not well defined, including the treatment dose range and duration; 2) rapid degradation of IL-10 in vivo necessitates large or repeated dosing that leads to off-target or side effects. This thesis addresses these major challenges through two complementary projects: defining dose‑dependent immunomodulation of IL-10 after MI and establishing a nanoparticle-based controlled‑release strategy for precise regulation of IL-10 treatment. First, we tested whether IL‑10 exhibits dose‑dependent effects on the phenotypes of macrophages, a key regulator of tissue inflammation, and cardiac remodeling after MI. In RAW264.7 Macrophage models, we quantified the classic M1/M2 phenotype polarization responses and cytokine secretion across a wide range of IL‑10 concentrations (0–1,000 ng/mL), using both post‑polarization and co‑stimulation paradigms. Second, we developed a heparin‑based L-10nanoparticle delivery platform (CoaNP) to protect IL‑10 and enable its localized controlled release. CoaNP loaded with IL-10 (CoaNP‑IL‑10) effectively prolonged IL‑10 bioactivity. When compared with equivalent doses of free, unprotected IL‑10, CoaNP‑IL‑10 more efficiently reduced inflammatory Macrophage polarization while promoting non‑inflammatory Macrophage polarization and enhancing phagocytic function in vitro. When administered intramyocardially in vivo, CoaNP‑IL‑10 reduced myocardial fibrosis and CD68⁺ phagocytic cell infiltration and limited ventricular dilation after MI. Altogether, my findings demonstrated the effectiveness of a precision cytokine therapy paradigm that combines dose optimization with targeted controlled release to maximize immunomodulation and cardiac recovery post‑MI while minimizing ineffective drug exposure and potential unwanted effects.
Subject Categories
Medicine and Health Sciences
Keywords
cardiac repair cytokine Macrophage myocardial infarction
Number of Pages
80
Publisher
University of South Dakota
Recommended Citation
Zhang, Jing, "Programming Macrophage Phenotypes and Promoting Ischemic Heart Repair with Precision Immunomodulatory Therapy" (2026). Dissertations and Theses. 395.
https://red.library.usd.edu/diss-thesis/395