Multiplexed targeting of miRNA-210 in stem cell-derived extracellular vesicles promotes selective regeneration in ischemic hearts

Abstract

Extracellular vesicles (EVs) are cell derivatives containing diverse cellular molecules, have various physiological properties and are also present in stem cells used for regenerative therapy. We selected a “multiplexed target” that demonstrates multiple effects on various cardiovascular cells, while functioning as a cargo of EVs. We screened various microRNAs (miRs) and identified miR-210 as a candidate target for survival and angiogenic function. We confirmed the cellular and biological functions of EV-210 (EVs derived from ASCmiR-210) secreted from adipose-derived stem cells (ASCs) transfected with miR-210 (ASCmiR-210). Under hypoxic conditions, we observed that ASCmiR-210 inhibits apoptosis by modulating protein tyrosine phosphatase 1B (PTP1B) and death-associated protein kinase 1 (DAPK1). In hypoxic endothelial cells, EV-210 exerted its angiogenic capacity by inhibiting Ephrin A (EFNA3). Furthermore, EV-210 enhanced cell survival under the control of PTP1B and induced antiapoptotic effects in hypoxic H9c2 cells. In cardiac fibroblasts, the fibrotic ratio was reduced after exposure to EV-210, but EVs derived from ASCmiR-210 did not communicate with fibroblasts. Finally, we observed the functional restoration of the ischemia/reperfusion-injured heart by maintaining the intercommunication of EVs and cardiovascular cells derived from ASCmiR-210. These results suggest that the multiplexed target with ASCmiR-210 is a useful tool for cardiovascular regeneration.

EFNA3 as a predictor of clinical prognosis and immune checkpoint therapy efficacy in patients with lung adenocarcinoma

“…Moreover, one study demonstrated that miR-210 can regulate the expression of EFNA3 to promote sensory axon regeneration in adult mice [ 48 ]. Importantly, several studies indicate that miRNA-210 from extracellular vesicles could regulate the expression of EFNA3 to promote angiogenesis in ischemic hearts [ 49 ], oral squamous cell carcinoma [ 34 ], acute myocardial infarction [ 49 ], and ischemic disease models [ 50 ]. These studies suggest that abnormal expression of miR-210 is a possible cause of high EFNA3 expression in LUAD.…”

Multiplexed targeting of microRNA in stem cell-derived extracellular vesicles for regenerative medicine

“…Coronary artery diseases, a representative cardiovascular disease, are caused by atherosclerosis and are known to cause arrhythmias and myocardial infarction. In order to maintain the homeostasis of various cells (cardiac cells, fibroblasts, lymphocytes, mast cells, and macrophages) present in the cardiovascular system and the difficulties in cardiac regeneration and repair ( 14 ), so stem cell-derived EV therapy is essential, especially the special treatment of EV-derived miRNAs functioned as multiplexed targeting.…”

“…Using a lentivirus, miRNA-EV system was constructed that can stably produce miRNA-210, which plays a pivotal role in cardiovascular cells, in adult stem cell EVs. It was shown that miRNA-210 in stem cell-derived EVs controlled cardiac cell death by targeting protein tyrosine phosphatase 1B (PTP1B) and death-associated protein kinase 1 (DAPK1), and also controlled angiogeneisis of vascular cells by targeting Ephrin A (EFNA3), with no effect on cardiac fibroblasts ( 14 ). Similarly, substances targeted by miRNA-133a expressed in adult CPC were discovered through bioinformatic prediction including BMF (Bcl-2 modifying factor) and BIM (Bcl2l11), which are potent proapoptotic factors, a serine threonine kinase STK4 (formerly Mst1) activated by oxidative stress, and Foxo1 that is a critical promotor of cardiomyocyte survival upon oxidative stress conditions.…”

“…EVs play a role in delivering functional genetic material to other cells, and it transmit various information surrounding it to neighboring cells (microenvironment), thereby activating cell-to-cell interaction as a mediator of cell communication ( 12 ). In particular, it has been known that microRNA (miRNA), a short RNA molecule that regulates several cellular processes through post-transcriptional gene silencing, communicates between neighboring cells, however it has reported recently that miRNAs have been commonly or artificially delivered by inducing multiplexed target into the microenvironment via EVs ( 13 , 14 ).…”

Long non-coding RNA HOMER3-AS1 drives hepatocellular carcinoma progression via modulating the behaviors of both tumor cells and macrophages

“…The ENCODE consortium shows that more than 80% of the human genome are transcribed into RNAs, whereas less than 2% of the human genome lastly encodes proteins [ 10 ]. Thus, the protein non-coding transcripts are significantly more diverse than protein-coding mRNAs [ 11 – 13 ]. Long non-coding RNAs (lncRNAs) are the most diverse class of non-coding transcripts, which also have diversely regulatory roles in various pathophysiological processes [ 14 – 19 ].…”