Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea.
Pusan National University Medical Research Institute, Pusan National University School of Medicine, Pusan 49241, Republic of Korea.
Mol Ther. 2021 Apr 7;29(4):1471-1486. doi: 10.1016/j.ymthe.2020.12.025. Epub 2020 Dec 19.
Mesenchymal stromal cells (MSCs) are considered as a promising therapeutic tool for liver fibrosis, a main feature of chronic liver disease. Because small extracellular vesicles (sEVs) harboring a variety of proteins and RNAs are known to have similar functions with their derived cells, MSC-derived sEVs carry out the regenerative capacities of MSCs. Human tonsil-derived MSCs (T-MSCs) are reported as a novel source of MSCs, but their effects on liver fibrosis remain unclear. In the present study, we investigated the effects of T-MSC-derived sEVs on liver fibrosis. The expression of profibrotic genes decreased in human primary hepatic stellate cells (pHSCs) co-cultured with T-MSCs. Treatment of T-MSC-sEVs inactivated human and mouse pHSCs. Administration of T-MSC-sEVs ameliorated hepatic injuries and fibrosis in chronically damaged liver induced by carbon tetrachloride (CCl). miR-486-5p highly enriched in T-MSC-sEVs targeting the hedgehog receptor, smoothened (Smo), was upregulated, whereas Smo and Gli2, the hedgehog target gene, were downregulated in pHSCs and liver tissues treated with T-MSC-sEVs or miR-486-5p mimic, indicating that sEV-miR-486 inactivates HSCs by suppressing hedgehog signaling. Our results showed that T-MSCs attenuate HSC activation and liver fibrosis by delivering sEVs, and miR-486 in the sEVs inactivates hedgehog signaling, suggesting that T-MSCs and their sEVs are novel anti-fibrotic therapeutics for treating chronic liver disease.
间充质基质细胞（MSCs）被认为是治疗肝纤维化的有前途的治疗工具，肝纤维化是慢性肝病的主要特征。由于含有各种蛋白质和 RNA 的小细胞外囊泡（sEVs）已知具有与其衍生细胞相似的功能，因此 MSC 衍生的 sEVs 发挥 MSC 的再生能力。人扁桃体衍生的 MSC（T-MSCs）被报道为 MSC 的新来源，但它们对肝纤维化的影响尚不清楚。在本研究中，我们研究了 T-MSC 衍生的 sEVs 对肝纤维化的影响。与人原代肝星状细胞（pHSCs）共培养时，促纤维化基因的表达降低。T-MSC-sEVs 处理可使人和鼠 pHSCs 失活。T-MSC-sEVs 的给药可改善四氯化碳（CCl）诱导的慢性受损肝脏中的肝损伤和纤维化。T-MSC-sEVs 中高度富集的 miR-486-5p 靶向 hedgehog 受体 smoothened（Smo），而上调，而 Smo 和 hedgehog 靶基因 Gli2 在 pHSCs 和用 T-MSC-sEVs 或 miR-486-5p 模拟物处理的肝组织中下调，表明 sEV-miR-486 通过抑制 hedgehog 信号来使 HSCs 失活。我们的结果表明，T-MSCs 通过递送 sEVs 减轻 HSC 激活和肝纤维化，并且 sEV 中的 miR-486 使 hedgehog 信号失活，提示 T-MSCs 和它们的 sEVs 是治疗慢性肝病的新型抗纤维化治疗方法。
