Macrophage heterogeneity in myocardial infarction: Evolution and implications for diverse therapeutic approaches

Abstract

Given the extensive participation of myeloid cells (especially monocytes and macrophages) in both inflammation and resolution phases post-myocardial infarction (MI) owing to their biphasic role, these cells are considered as crucial players in the disease pathogenesis. Multiple studies have agreed on the significant contribution of macrophage polarization theory (M2 vs. M1) while determining the underlying reasons behind the observed biphasic effects; nevertheless, this simplistic classification attracts severe drawbacks. The advent of multiple advanced technologies based on OMICS platforms facilitated a successful path to explore comprehensive cellular signatures that could expedite our understanding of macrophage heterogeneity and plasticity. While providing an overall basis behind the MI disease pathogenesis, this review delves into the literature to discuss the current knowledge on multiple macrophage clusters, including the future directions in this research arena. In the end, our focus will be on outlining the possible therapeutic implications based on the emerging observations.

Keywords: cardiovascular medicine; health sciences; human physiology.

Graphical abstract

Figure 1

Emerging dimensions in the understanding of the macrophage heterogeneity In the past decade, the area of macrophage heterogeneity was widely explored using different advancing technologies, which resulted in disseminating knowledge from different directions. The outcomes are comprehensive but undelineated, thus prompting future investigations. Created with BioRender.com.

Figure 2

Different sites for sources of macrophage heterogeneity in an infarcted heart An infarcted myocardium shows three functionally distinct regions, viz., infarct zone, per-infarct zone, and remote zone. Bone marrow and spleen act as the reservoirs to replenish the circulatory monocyte populations during MI, and multiple colors for depicting these cells indicate the possibility of multiple but distinctive monocyte populations entering the circulation. RCMs were shown with three different types of cells, which act as pillars upon further clustering of subsets that took place based on the presence or absence of other markers. Circulatory arrows around TIMD⁺ CCR2⁻ Mφ and MHC-II^hi CCR2⁻ Mφ indicate their ability to self-proliferate and renew locally in the heart. Apart from being the sources of global macrophage heterogeneity, all these sites may also act as the points of determination for spatiotemporal variations in macrophages. Created with BioRender.com.

Figure 3

Therapeutic implications of macrophage heterogeneity in an infarcted heart An infarcted heart consists of heterogeneous macrophage populations resulted from resident and monocyte-derived macrophage sources. Both temporal and spatial considerations determine the nature and type of heterogeneity involved, and such variations would form the basis behind their distinct functional effects, if exist. And this indeed acts as a rationale for developing personalized precision therapeutics based on patient-specific needs. Cardiac progenitors as primary or complementary therapies, cell-free therapeutic approaches such as extracellular vesicles (EVs), and design and development of targeted RNA-based silencing as well as small molecule inhibitors, all these approaches could be utilized for exploiting macrophage phenotype in the evolving framework of heterogeneity. Dotted lines indicate the need for further studies in this area of research. Created with BioRender.com.