From cerebral ischemia towards myocardial, renal, and hepatic ischemia: Exosomal miRNAs as a general concept of intercellular communication in ischemia-reperfusion injury

Abstract

Ischemia-reperfusion injury occurs when blood supply to an organ is disrupted-ischemia-and then restored-reperfusion-and is commonly found under different pathological settings such as cerebral, myocardial, renal, and hepatic ischemia-reperfusion injuries. Despite apparent differences as to the cause of these diseases, emerging evidence suggests that common signaling pathways, such as exosomes and microRNAs (miRNAs), are involved in this context. Although miRNAs are also found in the extracellular milieu, plenty of miRNAs are found in exosomes and are thus protected from degradation. miRNAs selectively sorted into exosomes potentially regulate specific aspects of the onset and progression of ischemic stroke. Such mechanisms involve the regulation of cell survival, inflammation, angiogenesis, and neurogenesis. Likewise, miRNAs shuttled into exosomes are involved in the pathogenesis of myocardial, renal, and hepatic ischemia-reperfusion injuries. This review will discuss recent evidence on the exosome-facilitated progression of four ischemia-reperfusion conditions, particularly concerning miRNAs within these vesicles. The notion is given to miRNAs participating in more than one of the four conditions, indicating a considerable degree of overlap across ischemia-reperfusion conditions. We will conclude the review by highlighting clinical opportunities of such exosome-derived miRNAs both as biomarkers and as therapeutic targets.

Graphical abstract

Figure 1

Role of central autonomic network and systemic inflammation in mediating renal and cardiac dysfunction after ischemic stroke (A) Ischemic stroke activates the hypothalamic-pituitary-adrenal axis, sympathetic nervous system, and the renin-angiotensin-aldosterone system, which regulate hormone and neurotransmitter release, thus resulting in kidney dysfunction. (B) Release of inflammatory factors by injured brain cells and increased oxidative stress can cause blood-brain barrier disruption, stroke-induced gut microbiome dysbiosis can transfer bacterial and endotoxin translocation to the blood, and the spleen can activate the immune cell, thereby leading to systemic inflammation. Systemic inflammation is central in promoting renal and cardiac dysfunction after stroke. (C) Ischemic stroke-induced activation of the hypothalamic-pituitary-adrenal axis and autonomic activation can alter the release of adrenal catecholamines and neural catecholamines, thus resulting in cardiac dysfunction. This image is adapted from a previous study published under the Creative Common attribution license.

Figure 2

The brief sorting mechanism of exosomal miRNA and uptake by recipient cells The biogenesis of miRNA involves transcription of a pri-miRNA, formation of pre-miRNA, translocation to the cytoplasm, and maturation of the miRNA. miRNAs containing different RNA motifs can be loaded into multivesicular bodies (MVBs) via different RNA-binding proteins. MVBs can either follow a degradation pathway fusing with lysosomes or release the intraluminal vesicles as exosomes to the extracellular space. Recipient cells can uptake exosomal miRNAs by three pathways: direct fusion, endocytosis, and receptor signaling.

Figure 3

The involvement of exosome-associated miRNAs in ischemic stroke Different donor cells, namely neurons, microglia, astrocytes, endothelial cells, serum, and MSCs, can regulate recipient cells by transferring a set of exosome-associated miRNAs, modulating biological behaviors including neuronal survival, inflammation, angiogenesis, and neurogenesis, therefore regulating ischemic stroke progression and recovery.

Figure 4

The involvement of exosome-associated miRNAs in myocardial infarction The recipient cells can internalize various exosome-associated miRNAs released from different donors, which modulate various biological responses, including cell survival, inflammation, angiogenesis, and fibrosis, thus regulating myocardial infarction progression and recovery. ADSC, adipose tissue-derived mesenchymal stromal cell.

Figure 5

The involvement of exosome-associated miRNAs in renal ischemia-reperfusion injury Various recipient cells can uptake a series of exosome-associated miRNAs derived from different donor cells, which alter several biological processes, namely cell survival, apoptosis, inflammation, and fibrosis, regulating myocardial infarction progression and recovery. USC, urine-derived stem cells.