Mesenchymal stem cell-derived exosomal miR-27b-3p alleviates liver fibrosis via downregulating YAP/LOXL2 pathway

Abstract

Lysyl oxidase-like 2 (LOXL2) is an extracellular copper-dependent enzyme that plays a central role in fibrosis by catalyzing the crosslinking and deposition of collagen. Therapeutic LOXL2 inhibition has been shown to suppress liver fibrosis progression and promote its reversal. This study investigates the efficacy and underlying mechanisms of human umbilical cord-derived exosomes (MSC-ex) in LOXL2 inhibition of liver fibrosis. MSC-ex, nonselective LOX inhibitor β-aminopropionitrile (BAPN), or PBS were administered into carbon tetrachloride (CCl4)-induced fibrotic livers. Serum LOXL2 and collagen crosslinking were assessed histologically and biochemically. MSC-ex’s mechanisms on LOXL2 regulation were investigated in human hepatic stellate cell line LX-2. We found that systemic administration of MSC-ex significantly reduced LOXL2 expression and collagen crosslinking, delaying the progression of CCl4-induced liver fibrosis. Mechanically, RNA-sequencing and fluorescence in situ hybridization (FISH) indicated that miR-27b-3p was enriched in MSC-ex and exosomal miR-27b-3p repressed Yes-associated protein (YAP) expression by targeting its 3ʹ untranslated region in LX-2. LOXL2 was identified as a novel downstream target gene of YAP, and YAP bound to the LOXL2 promoter to positively regulate transcription. Additionally, the miR-27b-3p inhibitor abrogated the anti-LOXL2 abilities of MSC-ex and diminished the antifibrotic efficacy. miR-27b-3p overexpression promoted MSC-ex mediated YAP/LOXL2 inhibition. Thus, MSC-ex may suppress LOXL2 expression through exosomal miR-27b-3p mediated YAP down-regulation. The findings here may improve our understanding of MSC-ex in liver fibrosis alleviation and provide new opportunities for clinical treatment.

Role of Exosomal Modulation of Macrophages in Liver Fibrosis

“…These exosomes have been found to inhibit TGF-1/SMAD signaling to inhibit LF and stimulate hepatocyte proliferation, leading to a protective effect on hepatocytes. 85 , 88 Similar anti-LF and hepatoprotective and regenerative effects were also observed with exosomes from various sources of MSCs, including bmMSCs, 89 , 90 hucMSCs, 91 , 92 hlMSCs, 93 induced pluripotent MSCs, 94 heMSCs, 95 blood-derived MSCs, 96 and adipose-derived MSCs of adipose origin. 97 Numerous studies have linked the anti-LF impact of macrophages to the exosomes derived from MSCs.…”

Engineered extracellular vesicle-encapsulated CHIP as novel nanotherapeutics for treatment of renal fibrosis

“…Over the past several years, the clinical studies of RIF therapies have concentrated on antifibrotic, including anti-fibrosis antibodies and YAP inhibitors 24 , 25 . Unfortunately, these treatment strategies have not achieved good results and were not significantly reduce fibrosis in clinical tests.…”

P65 mediated UBR4 in exosomes derived from menstrual blood stromal cells to reduce endometrial fibrosis by regulating YAP Ubiquitination

“…The Hippo pathway is highly conserved during evolution. A large amount of evidence has shown that the Hippo pathway plays an important regulatory role in the process of fibrosis of the liver and kidney, which are derived from mesoderm as the same as the uterus [ 45 , 46 ] and an in vitro study had shown that MenSCs could activate the Hippo pathway in EndoSCs through paracrine to inhibit the activation of fibroblasts and reduce TGF-β1-induced EndoSCs fibrosis [ 25 ]. Our previous results also found that MenSCs-EXO treatment decreased the expression level of YAP in the endometrium of IUA.…”