目的:尽管关于肝纤维化发生的细胞和分子机制的知识越来越多,目前尚无批准的治疗肝纤维化的药物。间充质干细胞(MSC)是多能祖细胞,代表了组织损伤和炎症的有吸引力的治疗工具。本研究旨在确定人脐带来源的MSCs(UC-MSCs)对硫代乙酰胺诱导的肝纤维化的保护作用和潜在机制。
方法:通过腹腔注射硫代乙酰胺(TAA)诱导小鼠肝纤维化。然后通过尾静脉注射UC-MSC或UC-MSC来源的外来体(UC-MSC-Exo)。收集肝组织用于组织学分析。
结果:我们发现给予UC-MSCs显著降低血清丙氨酸转氨酶和天冬氨酸转氨酶水平,和减轻肝脏炎症和纤维化。此外,UC-MSCs来源的外泌体的治疗效果与UC-MSCs相似.有趣的是,UC-MSCs-Exo治疗下调平滑(SMO)的表达,Hedgehog信号的一个基本组成部分,在纤维发生中起着关键作用,并随后抑制肝星状细胞的激活,实验性和人类肝损伤中纤维化的主要驱动因素。此外,在小鼠中,SMO激动剂SAG治疗逆转了UCMSCs-Exo的抗炎和抗纤维化作用.
结论:我们的发现表明UC-MSCs-Exo对肝纤维化发挥治疗作用,至少在某种程度上,通过抑制Hedgehog/SMO信号通路。
OBJECTIVE: Despite increasing knowledge regarding the cellular and molecular mechanisms of liver fibrogenesis, there is currently no approved drug for the treatment of liver fibrosis. Mesenchymal stem cells (MSCs) are multipotent progenitor cells representing an attractive therapeutic tool for tissue damage and inflammation. This study was designed to determine the protective effect and underlying mechanism of human umbilical cord-derived MSCs (UC-MSCs) on thioacetamide-induced liver fibrosis.
METHODS: Liver fibrosis was induced in mice by intraperitoneal injection of thioacetamide (TAA). Some mice were then given injection of UC-MSCs or UC-MSCs-derived exosomes (UC-MSCs-Exo) via the tail vein. Liver tissues were collected for histologic analysis.
RESULTS: We found that administration of UC-MSCs significantly reduced serum alanine aminotransferase and aspartate aminotransferase levels, and attenuated hepatic inflammation and fibrosis. Moreover, the therapeutic effect of UC-MSCs-derived exosomes was similar to that of UC-MSCs. Intriguingly, UC-MSCs-Exo treatment downregulated the expression of smoothened (SMO), a fundamental component of Hedgehog signaling which plays a critical role in fibrogenesis, and subsequently inhibited the activation of hepatic stellate cells, a central driver of fibrosis in experimental and human liver injury. Furthermore, the anti-inflammatory and anti-fibrotic effects of UCMSCs- Exo was reversed by the SMO agonist SAG treatment in mice.
CONCLUSIONS: Our findings suggest that UC-MSCs-Exo exert therapeutic effects on liver fibrosis, at least in part, through inhibiting the Hedgehog/SMO signaling pathway.