Elliot Sharon J, Anderson-Terhune Dustin, Roos Benjamin, Rubio Gustavo A, Xia Xiaomei, Pereira-Simon Simone, Catanuto Paola, Civettini Gina, Hagen Emily S, Arvanitis Constadina, Shahzeidi Shahriar, Glassberg Marilyn K
Stritch School of Medicine, Department of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.
Department of Pulmonary and Critical Care, University of Utah, Salt Lake City, UT 84112, USA.
Mol Ther Nucleic Acids. 2025 Jan 21;36(1):102461. doi: 10.1016/j.omtn.2025.102461. eCollection 2025 Mar 11.
Our previous work demonstrated the anti-fibrotic effects of infusion of adipose-derived mesenchymal stem cells (ASCs) to prevent or repair bleomycin (BLM)-induced lung injury. The present study investigates mechanisms driving these anti-fibrotic effects. Pulmonary fibrosis developed at day 12 in 22-month-old C57BL/6 male mice after intratracheal BLM instillation. There was a decrease in indices of pulmonary fibrosis, including collagen content, AKT activation, collagen types I and III, α-integrin, tumor necrosis factor alpha, and transforming growth factor β mRNA after infusion of ASCs 12 days post-BLM treatment compared to BLM alone. Infusion of ASCs increased the population of alveolar types I and II epithelial cells that had been reduced after BLM treatment. miRNAscope technology and reverse-transcription polymerase chain reaction revealed that ASC-treated mice demonstrated increased miR-29a, decreased miR-199, and increased telomere length, telomerase RNA component, and telomerase reverse transcriptase compared to BLM alone. and experiments using double-transfected mouse or human myofibroblasts (miR-29 mimic, and miR-199 inhibitor) confirmed that alterations of these miRNAs regulate downstream effectors of fibrosis. These data suggest that alteration of the ratio of anti-fibrotic to fibrotic miRNAs and increase in telomere length are critical mechanisms of ASC-mediated repair of BLM-induced pulmonary fibrosis.
我们之前的研究表明，输注脂肪来源的间充质干细胞（ASCs）可预防或修复博来霉素（BLM）诱导的肺损伤，具有抗纤维化作用。本研究探讨了驱动这些抗纤维化作用的机制。在22月龄C57BL/6雄性小鼠气管内滴注BLM后第12天出现肺纤维化。与单独使用BLM相比，在BLM治疗12天后输注ASCs后，肺纤维化指标有所下降，包括胶原蛋白含量、AKT激活、I型和III型胶原蛋白、α-整合素、肿瘤坏死因子α和转化生长因子β mRNA。输注ASCs增加了BLM治疗后减少的I型和II型肺泡上皮细胞数量。miRNAscope技术和逆转录聚合酶链反应显示，与单独使用BLM相比，接受ASC治疗的小鼠miR-29a增加、miR-199减少，端粒长度、端粒酶RNA组分和端粒酶逆转录酶增加。 使用双转染小鼠或人成肌纤维细胞（miR-29模拟物和miR-199抑制剂）的实验证实，这些miRNA的改变调节纤维化的下游效应器。这些数据表明，抗纤维化与促纤维化miRNA比例的改变以及端粒长度的增加是ASC介导的BLM诱导的肺纤维化修复的关键机制。
