Abstract
Background: Neonatal mice, but not older mice, can regenerate their hearts after myocardial-infarction (MI), a process mediated by pro-reparative macrophages. α-Gal nanoparticles applied to skin wounds in adult-mice bind the anti-Gal antibody, activate the complement cascade and generate complement chemotactic peptides that recruit pro-reparative macrophages which are further activated by these nanoparticles. The recruited macrophages decrease wound healing time by ~50%, restore the normal skin structure and prevent fibrosis and scar formation in mice.Objectives: The objective of this study is to determine if α-gal nanoparticles injected into the reperfused myocardium after MI in adult-mice can induce myocardial repair that restores normal structure, similar to that observed in skin injuries.Methods and Results: MI was induced by occluding the mid-portion of the left anterior descending (LAD) coronary artery for 30 min. Immediately following reperfusion, each mouse received two 10 μl injections of 100 μg α-gal nanoparticles in saline into the LAD territory (n = 20), or saline for controls (n = 10). Myocardial infarct size was measured by planimetry following Trichrome staining and macrophage recruitment by hematoxylin-eosin staining. Left ventricular (LV) function was measured by echocardiography. Control mice displayed peak macrophage infiltration at 4-days, whereas treated mice had a delayed peak macrophage infiltration at 7-days. At 28-days, control mice demonstrated large transmural infarcts with extensive scar formation and poor contractile function. In contrast, mice treated with α-gal nanoparticles demonstrated after 28-days a marked reduction in infarct size (~10-fold smaller), restoration of normal myocardium structure and contractile function.Conclusions: Intramyocardial injection of α-gal nanoparticles post-MI in anti-Gal producing adult-mice results in near complete repair of the infarcted territory, with restoration of normal LV structure and contractile function. The mechanism responsible for this benefit likely involves alteration of the usual inflammatory response post-MI, as previously observed with regeneration of injured hearts in adult zebrafish, salamanders and neonatal mice.
Highlights
Myocardial infarction (MI) is the cause of 25% of the deaths in the USA, primarily because of the extremely limited regenerative capacity of the myocardium [1]
We have previously reported that extensive immune mediated complement activation which results in macrophage recruitment, is associated with accelerated regeneration and prevention of fibrosis in skin injuries of adult mice treated with αgal nanoparticles [24,25,26,27,28,29]
Nanoparticles lacking α-gal epitopes do not bind anti-Gal produced by mouse or pig knockout for the α1 (GT-KO) mice
Summary
Myocardial infarction (MI) is the cause of 25% of the deaths in the USA, primarily because of the extremely limited regenerative capacity of the myocardium [1]. “pro-reparative” polarized macrophages secrete cytokines which orchestrate angiogenesis, fibrosis and scar formation In contrast to this repair mechanism, several vertebrates were found capable of natural regeneration of the injured myocardium, thereby restoring the original structure of the tissue without fibrosis. If injury to the heart in these mammalian neonates is caused during the first or second day after birth, the injured myocardium regenerates into its original structure, whereas injuries caused several days after birth result in fibrosis and scar formation as in the adult animal These myocardial regeneration processes in fish, amphibians and mammalian neonates were found to be associated with extensive infiltration of macrophages into the injured tissue [16,17,18,19,20] and activation of the complement system [20,21,22,23]. The recruited macrophages decrease wound healing time by ∼50%, restore the normal skin structure and prevent fibrosis and scar formation in mice
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