Development of a multi-organ-on-a-chip microfluidic system for ischemia/reperfusion injury

Introduction: Ischemic heart disease is the leading cause of death globally and is associated with significant health consequences for the individual and high medical costs for society. Timely reperfusion after myocardial infarction (MI) is the current standard therapy to limit damage to the ischemic region, however, reperfusion itself leads to paradoxical cardiomyocyte (CM) dysfunction and increase in myocardial damage, known as ischemic-reperfusion injury (IRI) (Heusch, Nat Rev Cardiol, 2020;17:773-789). Recently, landmark studies revealed that the healthy heart harbors cardiac resident macrophages, which clear up the dysfunctional mitochondria from CMs and play an important role in the maintenance of cardiac function (Nicolás-Ávila et al., Cell, 2020;183:94-109). However, upon MI, cardiac resident macrophages die alongside ischemic CMs and circulating monocyte-derived macrophages infiltrated the infarcted heart, which promote myocardial inflammation, maladaptive ventricular remodeling and subsequent heart failure (Dick et al., Nat Immunol, 2019;20:29-39; Bajpai et al., Circ Res, 2019;124:263-278). More and more studies demonstrate the remarkable heterogeneity and plasticity in macrophage development, phenotype, and function in the mouse heart. Similarly, by
analyzing of patients with sex-mismatched heart transplantation, different subsets of macrophages were found in the human heart. Whereas CCR2- macrophages are a cardiac tissue-resident population, CCR2+ macrophages are maintained through monocyte recruitment. The increased abundance of CCR2+ macrophages in the heart is associated with left ventricular remodeling and systolic dysfunction (Bajpai et al., Nat Med, 2018;24:1234-1245). These studies indicate a complex role of macrophages in the heart after MI and may explain the failure of non-specific immunosuppressive strategies in translation into clinical practice. Hence, understanding the role of diverse macrophages in protection of CM function may offer novel opportunities for therapeutic targeting to prevent heart failure after acute MI.