MiR‐20a‐containing exosomes from umbilical cord mesenchymal stem cells alleviates liver ischemia/reperfusion injury

Abstract

Mesenchymal stem cells (MSCs) have been proved to exert considerable therapeutic effects on ischemia‐reperfusion (I/R)‐induced injury, but the underlying mechanism remains unknown. In this study, we aimed to explore the potential molecular mechanism underlying the therapeutic effect of MSCs‐derived exosome reinforced with miR‐20a in reversing liver I/R injury. Quantitative real‐time polymerase chain reaction, Western blot, and IHC were carried out to compare the differential expressions of miR‐20a, Beclin‐I, FAS, Caspase‐3, mTOR and P62 in IR rats and normal rats. TUNEL was performed to assess IR‐induced apoptosis in IR rats, and luciferase assay was used to confirm the inhibitory effect of miR‐20a on Beclin‐I and FAS expression. Among the 12 candidate microRNAs (miRNAs), miR‐486, miR‐25, miR‐24, miR‐20a,miR‐466 and miR‐433‐3p were significantly downregulated in I/R. In particular, miR‐20a, a miRNA highly expressed in umbilical cord‐derived mesenchymal stem cells, was proved to bind to the 3ʹ UTR of Beclin‐I and FAS to exert an inhibitory effect on their expressions. Since Beclin‐I and FAS were aberrantly upregulated in IR, exosomes separated from UC‐MSCs showed therapeutic efficacy in reversing I/R induced apoptosis. In addition, exosomes reinforced with miR‐20a and separated from UC‐MSCs almost fully alleviated I/R injury. Furthermore, our results showed that miR‐20a could alleviate the abnormal expression of genes related to apoptosis and autophagy, such as active Caspase‐3, mTOR, P62, and LC3II. This study presented detailed evidence to clarify the mechanism underlying the therapeutic efficacy of UC‐MSCs in the treatment of I/R injury.

Microparticles derived from human erythropoietin mRNA-transfected mesenchymal stem cells inhibit epithelial-to-mesenchymal transition and ameliorate renal interstitial fibrosis

“…Previous MSC therapies have reported the selective homing of administered MSCs to the site of injury [22,39], consistent with our results showing the preferential engraftment of hEPO-MPs and their EPO mRNA contents to the inflammatory site of kidney injury, making this delivery platform highly attractive. Gene overexpression has been shown to enhance the therapeutic efficacy of MSC-derived MPs in various disease models [29,30]; therefore, using hEPO-MPs as a therapeutic strategy may be more convenient as well as physiologically relevant than systemic rhEPO administration. To our knowledge, our findings are the first to demonstrate that genetically modified hEPO-MPs could be used as a novel therapeutic agent to inhibit renal fibrosis.…”

Microparticles derived from human erythropoietin mRNA-transfected mesenchymal stem cells inhibit epithelial-to-mesenchymal transition and ameliorate renal interstitial fibrosis

“…Previous MSC therapies have reported the selective homing of administered MSCs to the site of injury [22,39], consistent with our results showing the preferential engraftment of hEPO-MPs and their EPO mRNA contents to the in ammatory site of kidney injury, making this delivery platform highly attractive. Gene overexpression has been shown to enhance the therapeutic e cacy of MSC-derived MPs in various disease models [29,30]; therefore, using hEPO-MPs as a therapeutic strategy may be more convenient as well as physiologically relevant than systemic rhEPO administration. To our knowledge, our ndings are the rst to demonstrate that genetically modi ed hEPO-MPs could be used as a novel therapeutic agent to inhibit renal brosis.…”

“…Since MP characteristics depend on the cell of origin and the external stimuli or injury, recent studies have used preconditioning or gene modi cation to enhance the therapeutic e cacy of MSC-derived MPs [26]. In particular, MPs derived from hypoxia-preconditioned MSCs promoted angiogenesis more than those derived from MSCs cultured under normoxic conditions [27,28], while gene overexpression enhanced the therapeutic e cacy of MSCderived MPs in various disease models [29,30]. Therefore, using MPs derived from EPO mRNA-overexpressing MSCs could be an appealing therapeutic strategy to effectively deliver EPO mRNA to target cells and promote tissue repair or regeneration.…”

Current Knowledge and Future Perspectives on Mesenchymal Stem Cell-Derived Exosomes as a New Therapeutic Agent

“…Exosomes from miR-223-overexpressing MSCs downregulated NLRP3 and caspase-1, and exhibited protective effects in injured hepatocytes and an experimental autoimmune hepatitis model [160]. Another study showed that exosomes from miR-20a-overexpressing MSCs downregulated beclin-I and FAS, and alleviated apoptosis and autophagy in a liver ischemia-reperfusion rat model [161]. In LPS-induced alveolar epithelial cells, exosomes from miR-30b-3p-overexpressing MSCs promoted cell proliferation and diminished cell apoptosis by downregulating SAA3.…”