PDF(Pubmed)
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 3\' 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.
摘要：
赖氨酰氧化酶样2（L0XL2）是一种细胞外铜依赖性酶，通过催化胶原蛋白的交联和沉积在纤维化中起重要作用。治疗性L0XL2抑制已显示抑制肝纤维化进展并促进其逆转。这项研究调查了人脐带衍生的外泌体（MSC-ex）在L0XL2抑制肝纤维化中的功效和潜在机制。MSC-ex,非选择性LOX抑制剂β-氨基丙腈（BAPN），或将PBS施用到四氯化碳(CCl4)诱导的纤维化肝脏中。对血清L0XL2和胶原交联进行组织学和生化评估。在人肝星状细胞系LX-2中研究了MSC-ex对LOXL2调节的机制。我们发现，MSC-ex的全身给药显著降低L0XL2表达和胶原交联，延缓CCl4诱导的肝纤维化的进展。机械上,RNA测序和荧光原位杂交（FISH）表明，miR-27b-3p富集在MSC-ex和外泌体miR-27b-3p中，通过靶向其3'非翻译区抑制Yes相关蛋白（YAP）的表达。LX-2。L0XL2被鉴定为YAP的一个新的下游靶基因,和YAP结合到L0XL2启动子以正向调节转录。此外,miR-27b-3p抑制剂消除了MSC-ex的抗L0XL2能力,并降低了抗纤维化功效.miR-27b-3p过表达促进MSC-ex介导的YAP/L0XL2抑制。因此，MSC-ex可能通过外泌体miR-27b-3p介导的YAP下调抑制L0XL2表达。这些发现可能会提高我们对MSC-ex在肝纤维化缓解中的理解，并为临床治疗提供新的机会。
