Cellular signaling cross-talk between different cardiac cell populations: an insight into the role of exosomes in the heart diseases and therapy

Abstract

Exosomes are a subgroup of extracellular bilayer membrane nanovesicles that are enriched in a variety of bioactive lipids, receptors, transcription factors, surface proteins, DNA, and noncoding RNAs. They have been well recognized to play essential roles in mediating intercellular signaling by delivering bioactive molecules from host cells to regulate the physiological processes of recipient cells. In the context of heart diseases, accumulating studies have indicated that exosome-carried cellular proteins and noncoding RNA derived from different types of cardiac cells, including cardiomyocytes, fibroblasts, endothelial cells, immune cells, adipocytes, and resident stem cells, have pivotal roles in cardiac remodeling under disease conditions such as cardiac hypertrophy, diabetic cardiomyopathy, and myocardial infarction. In addition, exosomal contents derived from stem cells have been shown to be beneficial for regenerative potential of the heart. In this review, we discuss current understanding of the role of exosomes in cardiac communication, with a focus on cardiovascular pathophysiology and perspectives for their potential uses as cardiac therapies.

Keywords: cardiac remodeling; exosomes; fibrosis; inflammation; stem cells.

Figure 1.

Typical structure of exosomes, including key membrane proteins and components of the exosome cargo such as nucleic acids, cytosolic proteins, amino acids, and biogenesis proteins.

Figure 2.

Biogenesis of exosomes. Membrane invagination (1) results in the formation of an endocytic vesicle known as early endosome (2), which matures into the late endosome (3). Subsequently, the Golgi apparatus and endoplasmic reticulum incorporate various bioactive molecules into the late endosome, producing the multivesicular body (MVB) (4). The MVB can then either undergo degradation via the lysosome or autophagosome or fuse with the plasma membrane to release exosomes into the extracellular environment (5).

Figure 3.

Illustration of the exosome-mediated cross-talk among cardiomyocytes and other cardiac cell types in the heart, such as fibroblasts, macrophages, and adipocytes, during hypertrophic signaling.Under angiotensin II and pressure overload stresses, exosomes derived from fibroblasts (A) and macrophages (B) containing miR-21* and miR-155, respectively, can downregulate SPRBS2, PDLIM5, and Socs1 and activate several components of angiotensin signaling pathway in cardiomyocytes, eventually resulting in the development of hypertrophy. C: adipocytes could remotely enhance cardiac hypotrophy by mTOR activation-meditated exosomal miR-200a expression in response to rosiglitazone treatment.

Figure 4.

The origin and the pathological stress subjected to cells can determine whether exosomes can protect against fibrosis or encourage fibrosis formation via various miRNA signaling. Cardiomyocytes (A) can induce cardioprotection by attenuating fibrogensis during hypoxic conditions and type 2 diabetes by releasing exosomes containing lncRNA AK139128 or miR-29b, miR-455, and HSP20, respectively. In contrast, exosomes derived from macrophages subjected to pressure overload or myocardial infraction (B) contain miR-155, which can exacerbate the accumulation of fibrosis by stimulating myofibroblast formation by increasing TGFβ. Similarly, exosomes released from cardiomyocytes (C) in response to angiotensin II typically contain miR-208a and miR-217 to increase extracellular matrix remodeling.

Figure 5.

The roles of exosomes in the antioxidant and apoptotic signaling pathways. A: exosome shuttling between cardiomyocytes and fibroblasts containing various miRNAs such as miR027a, miR-28-3p, and miR-34a can be attributable to reactive oxygen species (ROS) overproduction during cardiac diseases such as pressure overload and myocardial infarction by repressing Nrf2 expression, an antioxidant arm. B: in remote ischemic preconditioning (RIPC), plasma-derived exosomes can protect cardiomyocytes against apoptosis by increasing ERK1/2/Akt/Hsp27 to promote activation of prosurvival pathways. In contrast, exosomes from cardiomyocytes subjected to hypoxia (C) contain miR-30a and can cross-talk between other cardiomyocytes to decrease the autophagy response and increase apoptosis. D: platelet-derived exosomes can also induce apoptosis in cardiomyocytes by increasing caspase-3 activity to increase apoptosis.

Figure 6.

Exosome-mediated signaling involved in angiogenic signaling pathways. Under physiological conditions (A), cardiomyocytes and telocytes release exosomes containing various miRNAs and bioactive molecules that promote proangiogenic signaling. Similarly, exosomes derived from cardiomyocytes subjected to hypoxic conditions or glucose deprivation (B) contain various miRNAs that increase proangiogenic signaling pathways to stimulate endothelial cells to increase angiogenesis. In contrast, exosomes derived from cardiomyocytes subjected to pressure overload or type 2 diabetes (C) typically contain miR-300c and miR-320, which promote the antiangiogenic pathway. D: similarly, in peripartum cardiomyopathy, endothelial cell-derived exosomes can induce endothelial cells to downregulate several components of the proangiogenic signaling pathway, leading to impaired angiogenesis. VEGF, vascular endothelial growth factor; FGF, fibroblast growth factor; NO, nitric oxide.

Figure 7.

Stem cell-derived exosomes hold potential cell-free therapies for myocardial infarction by enhancing angiogenesis, cardiomyocyte survival and proliferation, and repressing fibrosis, inflammatory responses, and apoptosis. Mesenchymal stem cells (MSCs), cardiac progenitor cells (CPCs), cardiosphere-derived cells (CDCs), induced pluripotent stem cells (iPSCs), hematopoietic stem cells (HSCs), and adipocyte-derived stem cells (ADSCs) release exosomes containing various bioactive molecules, including miRNA, which can act upon cells of the cardiovascular system including cardiomyocytes, fibroblasts, and endothelial cells. In turn, they can inhibit or promote key processes involved in cardiovascular disease to change the disease outcome.