Ischemic tolerance and cardiac repair in the spiny mouse (Acomys)

Tim Koopmans,Olympia E Psathaki,Divyanshu Malhotra,Jochem Boeter,Danielle Versteeg,Henriette Van Beijnum,Kerstin Bartscherer,Eva Van Rooij,Antonio Tomasso,Elke F Roovers

doi:10.1038/s41536-021-00188-2

Abstract

Ischemic heart disease and by extension myocardial infarction is the primary cause of death worldwide, warranting regenerative therapies to restore heart function. Current models of natural heart regeneration are restricted in that they are not of adult mammalian origin, precluding the study of class-specific traits that have emerged throughout evolution, and reducing translatability of research findings to humans. Here, we present the spiny mouse (Acomys spp.), a murid rodent that exhibits bona fide regeneration of the back skin and ear pinna, as a model to study heart repair. By comparing them to ordinary mice (Mus musculus), we show that the acute injury response in spiny mice is similar, but with an associated tolerance to infarction through superior survivability, improved ventricular conduction, and near-absence of pathological remodeling. Critically, spiny mice display increased vascularization, altered scar organization, and a more immature phenotype of cardiomyocytes, with a corresponding improvement in heart function. These findings present new avenues for mammalian heart research by leveraging unique tissue properties of the spiny mouse.

Highlights

Heart failure affects more than 26 million people worldwide[1], making effective therapies to treat cardiac disease a major public health goal
Despite an initial scar forming response and corresponding drop in heart function that is similar between the species, spiny mice exhibit significant tolerance to infarction, demonstrated by superior survivability, retainment of ventricular conduction, and near-absence of pathological remodeling
B6 took on body weight more rapidly than Ac, we found that the MI procedure had no add-on effect on body weight compared to sham-controls, for both species (Supplementary Fig. 1c)

Summary

Introduction

Heart failure affects more than 26 million people worldwide[1], making effective therapies to treat cardiac disease a major public health goal. A key underlying cause of heart failure is the inability of the adult human myocardium to regenerate following injury combined with progressive deterioration known as pathological remodeling. A central focus in cardiac regenerative research has been the restoration of heart lineages, including vascular cells, support cells, and most notably, cardiomyocytes. Its effectiveness has been limited by the absence of naturally regenerating adult mammalian organisms[2], restricting research to either non-mammalian vertebrates (such as zebrafish3,4) or neonatal mice, which are capable of scar-free cardiac repair up to 1 week after birth[5]. Despite an initial scar forming response and corresponding drop in heart function that is similar between the species, spiny mice exhibit significant tolerance to infarction, demonstrated by superior survivability, retainment of ventricular conduction, and near-absence of pathological remodeling. Acomys hearts display a partial recovery in contractile output, a phenomenon associated with increased vascularization and altered scar organization

Methods

Results

Conclusion