Cardiovascular disease is the leading cause of mortality in the world with over 17 million deaths in 2008 alone, which is estimated to increase to over 23 million by 2030 and to remain the leading cause of deaths. Coronary heart disease causes the majority of deaths in cardiovascular disease with myocardial infarction (MI) often leading to the development of heart failure. MI is caused by occlusion of a coronary artery, which leads to a deficiency of oxygen and nutrients at the site of infarction and the subsequent death of cardiomyocytes. The exposure of danger-associated molecular patterns (DAMPs) from dead cardiomyocytes triggers the migration of neutrophils, monocytes, dendritic cells, lymphocytes and other cells with the subsequent initiation of inflammation, oxidative stress, tissue regeneration and cardiac remodeling; however, the mechanisms behind these processes are still not fully understood. Stem cell therapy is considered a promising approach in treating coronary heart disease including MI, largely due to trophic factors secreted by transplanted stem cells (paracrine effect) which influence host cell migration, cellular functions, cardiomyocyte survival, tissue regeneration and healing. However, conventional stem cell therapy for MI requires personalized stem cell isolation and lengthy in vitro expansion, which are cost- and time-consuming. The use of stem cell-derived trophic factors may lead to equally effective therapeutic approaches, substituting the need for stem cell transplantation.
Transplanted stem/progenitor cells improve tissue healing and regeneration anatomically and functionally mostly due to their secreted trophic factors. However, harsh conditions at the site of injury, including hypoxia, oxidative and inflammatory stress, increased fibrosis and insufficient angiogenesis, and in some cases immunological response or incompatibility, are detrimental to stem cell survival. To overcome the complexity and deficiencies of stem cell therapy, the coacervate delivery platform is deemed promising because it offers controlled and sustained release using heparin to recapitulate the binding and stabilization of extracellular proteins by heparan sulfates in native tissues. In this project, we show that recombinant alternatives of three key factors (VEGF, MCP-1 and IL-6), commonly produced by perivascular stem cells under various stress conditions, can be successfully incorporated into a heparin-based coacervate. We characterized the release profile of the triply incorporated factors from the complex coacervate. The coacervate-released factors were able to exert their desired biological activities in vitro: VEGF stimulated human umbilical vein endothelial cell proliferation, MCP-1 elevated macrophage migration, and IL-6 increased IgM production by IL-6 dependent cell line. Thus, a controlled release system can be used for simultaneous delivery of three stem cell-derived factors, and could be useful for tissue repair and regenerative medicine.
|Effective start/end date||1/1/14 → 12/31/17|