Chapter 14 - Post Infarction Regeneration of Ischemic Myocardium by Intramyocardial Injection of α-Gal Nanoparticles

Abstract

This chapter describes the possible use of α-gal nanoparticles in a hypothetical therapy that harnesses the natural anti-Gal antibody for inducing regeneration of the myocardium postmyocardial infarction (MI). α-Gal nanoparticles are biodegradable submicroscopic liposomes that present multiple α-gal epitopes (1015 epitopes/mg). These epitopes readily bind the natural anti-Gal antibody and activate the complement system, which generates complement cleavage peptides C5a and C3a that are very effective chemotactic factors for recruitment of macrophages. Recruited macrophages bind anti-Gal-coated α-gal nanoparticles via Fc/Fcγ receptors interaction and polarize into M2 anti-inflammatory, prohealing macrophages. Macrophages are pivotal cells in the regeneration of ischemic myocardium. They recruit stem cells, which are directed by the extracellular matrix (ECM) and microenvironment within the ischemic myocardium to differentiate into cardiomyocytes. α-Gal nanoparticles injected into the myocardium of anti-Gal producing α1,3galactosyltransferase knockout mice, and pigs were found to induce extensive migration of macrophages. Based on preliminary studies in these experimental models, it is suggested that intramyocardial injection of α-gal nanoparticles into post-MI myocardium by a catheter, shortly after the ischemia event, will induce rapid recruitment and activation of macrophages. These macrophages will secrete cytokines/growth factors that further induce vascularization of the ischemic myocardium, prevention of necrosis, and conservation of the microenvironment, including the myocardium ECM, and mediate recruitment of stem cells. The recruited stem cells will be “instructed” by the myocardial microenvironment and ECM to differentiate into cardiomyocytes that repopulate the ischemic myocardium and restore its structure and function. Because of the rapid recruitment and activation of macrophages by the injected α-gal nanoparticles, this regenerative process may occur prior to the default fibrosis of the myocardium and thus, prevent the irreversible development of a scar tissue. Suggested studies, which may prove this hypothesis, are discussed as well.