Macrophages in cardiac repair: Environmental cues and therapeutic strategies

Abstract

Mammals, in contrast to urodeles and teleost fish, lose the ability to regenerate their hearts soon after birth. Central to this regenerative response are cardiac macrophages, which comprise a heterogeneous population of cells with origins from the yolk sac, fetal liver, and bone marrow. These cardiac macrophages maintain residency in the myocardium through local proliferation and partial replacement over time by circulating monocytes. The intrinsic plasticity of cardiac macrophages in the adult heart promotes dynamic phenotypic changes in response to environmental cues, which may either protect against injury or promote maladaptive remodeling. Thus, therapeutic strategies promoting myocardial repair are warranted. Adult stromal cell-derived exosomes have shown therapeutic promise by skewing macrophages toward a cardioprotective phenotype. While several key exosomal non-coding RNA have been identified, additional factors responsible for cardiomyocyte proliferation remain to be elucidated. Here I review cardiac macrophages in development and following injury, unravel environmental cues modulating macrophage activation, and assess novel approaches for targeted delivery.

Fig. 1. Macrophages orchestrate the regenerative process post-MI.

Resident and non-resident macrophages respond to environmental cues released from the ischemic myocardium and secrete pro-regenerative factors to cardiac cell populations. DAMPS danger-associated molecular patterns, ECM extracellular matrix

Fig. 2. Exosome biogenesis and release.

a, Exosome production follows a stepwise sequence of events. (i), inward invagination of the plasma membrane to form an endosome; (ii), loading of exosomal cargo into the endosome, which leads to the formation of a multivisicular body (MVB); (iii), transport of the MVB to the membrane; and (iv), fusion of the MVB to the plasma membrane releasing exosomes. (v), MVBs not destined for extracellular release fuse with lysosomes for degradation. b, Exosomes contain an abundance of cargo reflective of the cell of origin. ER Endoplasmic reticulum

Fig. 3. Bioengineering exosomes for targeted therapeutics.

a Exosomes from unmodified (naïve) adult stem cells can be collected in vitro following a period of conditioning. b Cells can be modified to overexpress and incorporate distinct targeting proteins into the exosomal membrane. c Naïve exosomes may be collected and modified after purification for targeted delivery. DPS: DMPE-PEG-streptavidin

Fig. 4. Multipronged therapeutic approach for MI.

Bioengineered exosomes with curated cargo and membrane tags can be delivered intravenously (i.v.). Exosomes home to the site of injury and modify the targeted cell for repair. FB Fibroblast, EC Endothelial cell, CM Cardiomyocyte, M Macrophage, SMC Smooth muscle cell