Targeted Delivery of Factors and Cells for Improving Cardiac Tissue Regeneration and Heart Function Following Myocardial Infarction

Collaborative Research Program 2021-2023

Cardiovascular diseases (CVD) are the leading cause of mortality worldwide [1]. In 2017, about 17.8 million deaths globally were attributed to CVD [2]. In addition, quality of life is also significantly affected in patients with CVD health problems [3]. Despite advancements in medicine, mortality rates are rising in some groups. This is due to a combination of healthcare system issues and an increase in risk factors [1]. According to the American Heart Association, medical and productivity loss costs of CVD are expected to increase from $555 billion in 2015 to $1.1 trillion in 2035. In addition, the estimated informal care cost is also expected to grow from $616 billion in 2015 to $1.2 trillion in 2035 with 45% of the US population developing CVD by that time [4]. In the European Union, the total cost in 2017 was €210 billion where 53% is direct, 26% is productivity loss, and 21% is informal care cost [3]. The European Society of Cardiology puts Kazakhstan in the list of countries with a very high risk of fatal CVD development in healthy people in a 10-year period [5]. Moreover, 50% of mortality cases in Kazakhstan in 2016 were associated with CVD [6]. Coronary heart disease causes the majority of deaths in CVD with myocardial infarction (MI) often leading to heart failure. Understanding the role of the innate and adaptive immune systems in MI helps researchers and clinicians identify potential molecular and/or cellular therapeutic targets for immunomodulatory MI therapy. Injury at the site of infarction triggers acute inflammation and subsequent inflammatory responses, including migration of neutrophils and pro-inflammatory monocytes, digestion of necrotic cells and cell debris, release of reactive oxygen species, and generation of oxidative stress. These sequelae further aggravate inflammation but are typically followed by the migration and differentiation of reparative monocytes/macrophages, production of collagen, and angiogenesis, resulting in nonfunctional healing of the infarcted myocardium [7, 8]. Stem cell therapy is considered a promising approach in treating coronary heart disease including MI. 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, drug delivery systems are deemed promising because they offer a controlled and sustained release of bound growth factors and cytokines. Moreover, targeted delivery of stem cells preconditioned with hypoxia and/or oxidative/inflammatory stimuli or pre-differentiated cells in combination with controlled release of immunomodulatory and wound healing factors will treat myocardial infarction more effectively than the transfer of factors alone, by reducing the infarct size and inflammation, and generating more functional heart tissue. Thus, the goals of this project are to develop chitosan-based microparticles for controlled delivery of factors, investigate the efficacy of targeted delivery and controlled release of immune system modulatory and wound healing factors in combination with preconditioned stem cells or predifferentiated cells for improving tissue regeneration and heart function, and study the mechanisms by which incorporated factors/cells mediate their effects and ameliorate inflammation following MI. This project should both increase our understanding of the mechanisms of incorporated factor and/or cell-mediated cardiac repair, as well as facilitate the development of new technologies for improving cardiac tissue regeneration and repair. As a result, new therapeutic approaches in the area of regenerative medicine will be developed to save human lives, improve quality of life and reduce healthcare costs in Kazakhstan and beyond.